2-imino-1,3-thiazine derivatives

ABSTRACT

The present invention relates to 2-imino-1,3-thiazine derivatives, in specific, 2-imino-1,3-thiazine derivatives having a selective antagonistic activity or agonistic activity to a cannabinoid type 2 receptor and their pharmaceutical use.

TECHNICAL FIELD

The present invention relates to 2-imino-1,3-thiazine derivatives, in detail, 2-imino-1,3-thiazine derivatives having a selective antagonistic activity or agonistic activity to a cannabinoid type 2 receptor and pharmaceutical use of themselves.

BACKGROUND ART

Cannabinoid was discovered as the main active substance contained in marijuana in 1960 and found to exhibit an activity to the central nervous system (illusion, euphoria, sensory confusion of time and space) and an activity to the peripheral cell system (immunosuppressive activity, anti-inflammatory activity, analgesic activity).

After that, anandamide and 2-arachidonoylglycerol produced from phospholipid containing arachidonic acid were discovered as endogenous agonists to a cannabinoid receptor. These endogenous agonists were known to exhibit an activity to the central nervous system and an activity to the peripheral cell system. It was disclosed in Hypertension (1997) 29, 1204-1210 that anandamide exhibits an activity to the cardiovascular system.

A cannabinoid type 1 receptor discovered in 1990 was found to distribute in the central nervous system such as the brain. Agonists to this receptor were found to suppress the release of neurotransmitters to cause central actions such as illusion or the like. A cannabinoid type 2 receptor discovered in 1993 was found to distribute in immune tissues such as the spleen or the like. Agonists to this receptor were found to suppress an activation of cells in immunocyte or phlogocyte to exhibit an immunosuppressive activity, an anti-inflammatory activity and an analgesic activity (Nature, 1993, 365, 61-65).

Therefore, selective antagonists or agonists to the cannabinoid type 2 receptor are expected as immunosuppressive agents, anti-inflammatory agents, analgesic agents without causing side effects on the central nervous system such as illusion or the drug dependence, which are associated with the cannabinoid type 1 receptor (Nature, 1998, 349, 277-281).

Known as compounds having an antagonistic activity or agonistic activity to the cannabinoid type 2 receptor are isoindolynone derivatives (WO97/29079 and WO99/02499), pyrazole derivatives (WO98/41519) and the like

On the other hand, Japanese Patent Publications (Kokai 1986-65894, Kokai 1987-29594) disclose that organophosphorus compounds having a 2-imino-1,3-thiazine skeleton are useful as insecticides.

However, it is not known that 2-imino-1,3-thiazine derivatives have an antagonistic activity or agonistic activity to the cannabinoid type 2 receptor.

DISCLOSURE OF INVENTION

The present invention provides 2-imino-1,3-thiazine derivatives or the like as novel compounds having a selective antagonistic activity or agonistic activity to the cannabinoid type 2 receptor.

The present invention comprises, 1) a pharmaceutical composition which comprises a compound of the formula (I):

wherein R¹ is optionally substituted alkylene, R² is alkyl; a group of the formula: —C(═R⁵)—R⁶ wherein R¹ is O or S, and R⁶ is alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aralkyloxy, optionally substituted aralkylthio, optionally substituted aralkylamino, alkoxyalkyl, alkylthioalkyl or optionally substituted aminoalkyl; or a group of the formula: —SO₂R⁷ wherein R⁷ is alkyl, optionally substituted amino, optionally substituted aryl or optionally substituted heteroaryl, m is an integer of 0 to 2, A is optionally substituted aromatic carbocycle or optionally substituted aromatic heterocycle, a prodrug of itself, a pharmaceutically acceptable salt thereof or a solvate thereof, 2) the pharmaceutical composition according to the above 1) wherein the group of the formula:

is a group of the formula:

wherein R³ and R⁴ each is independently hydrogen, alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, cycloalkyl, halogen, hydroxy, nitro, haloalkyl, haloalkoxy, optionally substituted carbamoyl, carboxy, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxyalkyl, alkylthioalkyl, optionally substituted aminoalkyl, alkoxyalkoxy, alkylthioalkoxy, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclic group, alkoxyiminoalkyl or a group of the formula: —C(═O)—R^(H) wherein R^(H) is hydrogen, alkyl, optionally substituted aryl or optionally substituted non-aromatic heterocyclic group, or R³ and R⁴ taken together may form alkylenedioxy, A is optionally substituted aromatic carbocycle or optionally substituted aromatic heterocycle, 3) the pharmaceutical composition according to the above 1) or 2) which has a binding activity to a cannabinoid type 2 receptor, 4) the pharmaceutical composition according to the above 3) which has an agonistic activity to a cannabinoid type 2 receptor, 5) the pharmaceutical composition according to the above 3) which is useful as an anti-inflammatory agent, 6) the pharmaceutical composition according to the above 3) which is useful as an immunosuppressive agent, 7) the pharmaceutical composition according to the above 3) which is useful as a nephritis treating agent, 8) a compound of the formula (II):

wherein R¹ is optionally substituted alkylene, R² is a group of the formula: —C(═R⁵)—R⁶ wherein R⁵ is O or S, R⁶ is alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aralkyloxy, optionally substituted aralkylthio, optionally substituted aralkylamino, alkoxyalkyl, alkylthioalkyl or optionally substituted aminoalkyl, or a group of the formula: —SO₂R⁷ wherein R⁷ is alkyl, optionally substituted amino, optionally substituted aryl or optionally substituted heteroaryl, R³ and R⁴ each is independently hydrogen, alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, cycloalkyl, halogen, hydroxy, nitro, haloalkyl, haloalkoxy, optionally substituted carbamoyl, carboxy, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxyalkyl, alkylthioalkyl, optionally substituted aminoalkyl, alkoxyalkoxy, alkylthioalkoxy, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclic group, alkoxyiminoalkyl, or a group of the formula: —C(═O)—R^(H) wherein R^(H) is hydrogen, alkyl, optionally substituted aryl or optionally substituted non-aromatic heterocyclic group, or R³ and R⁴ taken together may form alkylenedioxy, m is an integer of 0 to 2, A is optionally substituted aromatic carbocycle or optionally substituted aromatic heterocycle, a prodrug of itself, a pharmaceutically acceptable salt thereof or a solvate thereof, 9) the compound according to the above 8) wherein m is 0, a prodrug of itself, a pharmaceutically acceptable salt thereof or a solvate thereof, 10) the compound according to the above 8) or 9) wherein R¹ is a C2-C9 straight or branched alkylene optionally substituted with alkylene, a prodrug of itself, a pharmaceutically acceptable salt thereof or a solvate thereof, 11) the compound according to any one of the above 8) to 10) wherein R¹ is a C2-C9 straight alkylene substituted with alkylene, or a C2-C9 branched alkylene, a prodrug of itself, a pharmaceutically acceptable salt thereof or a solvate thereof, 12) the compound according to any one of the above 8) to 11) wherein R⁶ is alkoxy or alkylthio, and R⁷ is optionally substituted aryl, a prodrug of itself, a pharmaceutically acceptable salt thereof or a solvate thereof, 13) the compound according to any one of the above 8) to 12) wherein R³ and R⁴ each is independently hydrogen, alkyl, alkoxy or alkylthio, and A is optionally substituted aromatic carbocycle, a prodrug of itself, a pharmaceutically acceptable salt thereof or a solvate thereof, 14) the compound according to the above 8) wherein R¹ is 2,2-dimethyltrimethylene, 2,2-diethyltrimethylene, 2,2-ethylenetrimethylene, 1-methyltrimethylene, 2-methyltrimethylene, trimethylene, 2,2-di-n-propyltrimethylene, 2,2-tetramethylenetrimethylene, 2,2-pentamethylenetrimethylene, 1,1-dimethylethylene or 1-methylethylene, R⁶ is methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, methylthio, ethylthio, n-propylthio, i-propylthio, i-butylthio, sec-butylthio, benzyloxy, benzylthio, methoxymethyl, ethoxymethyl, methylthiomethyl, ethylthiomethyl or ethylamino, R⁷ is methyl, ethyl, 4-tolyl, 4-nitrophenyl, 3-nitrophenyl, 2-nitrophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-thienyl or 2-naphthyl, R³ is hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, methylthio, ethylthio, n-propylthio, i-propylthio, dimethylamino, acetylamino, N-acetylmethylamino, diethylamino, ethylmethylamino, propylmethylamino, phenyl, phenoxy, fluoro, chloro, bromo, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, N-methylcarbamoyl, methoxycarbonyl, methanesulfinyl, ethanesulfinyl, methanesulfonyl, ethanesulfonyl, acetyl, methoxymethyl, 1-methoxyethyl, 3-pyridyl, morpholino, pyrrolidino, piperidino, 2-oxopyrrolidino, 1-methoxyiminoethyl or morpholinocarbonyl, R⁴ is hydrogen, methyl, ethyl, fluoro, chloro, nitro, methoxy or ethoxy, or R³ and R⁴ taken together may form —O—CH₂—O—, A is benzene, naphthalene, pyridine or quinoline, a prodrug of itself, a pharmaceutically acceptable salt thereof or a solvate thereof, 15) a pharmaceutical composition which comprises the compound according to any one of the above 8) to 14), a prodrug of itself, a pharmaceutically acceptable salt thereof or a solvate thereof, 16) the pharmaceutical composition according to the above 15) which has a binding activity to a cannabinoid type 2 receptor, 17) the pharmaceutical composition according to the above 16) which has an agonistic activity to a cannabinoid type 2 receptor, 18) the pharmaceutical composition according to the above 16) which is useful as an anti-inflammatory agent, 19) the pharmaceutical composition according to the above 16) which is useful as an immunosuppressive agent, 20) the pharmaceutical composition according to the above 16) which is useful as a nephritis treating agent, 21) a method for treating inflammation which comprises administering the pharmaceutical composition according to the above 1), 22) a method of immunosuppression which comprises administering the pharmaceutical composition according to the above 1),

23) a method for treating nephritis which comprises administering the pharmaceutical composition according to the above 1),

24) use of the compound according to the above 1) for manufacturing an anti-inflammatory agent,

25) use of the compound according to the above 1) for manufacturing an immunosuppressive agent, and

26) use of the compound according to the above 1) for manufacturing a nephritis treating agent.

BEST MODE FOR CARRYING OUT THE INVENTION

The meanings of each term used in compound of the formula (I) and (II) are explained below. Each term is used to express the same meaning in the specification.

The term “alkylene” includes a C2-C10 straight or branched alkylene, for example, ethylene, 1-methylethylene, 1-ethylethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1,1-diethylethylene, 1,2-diethylethylene, 1-ethyl-2-methylethylene, trimethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 1,1-diethyltrimethylene, 1,2-diethyltrimethylene, 2,2-diethyltrimethylene, 2-ethyl-2-methyltrimethylene, tetramethylene, 1-methyltetramethylene, 2-methyltetramethylene, 1,1-dimethyltetramethylene, 1,2-dimethyltetramethylene, 2,2-dimethyltetramethylene, 2,2-di-n-propyltrimethylene or the like. Preferred is a C2-C9 straight or branched alkylene. More preferred is a C2-C9 branched alkylene, for example, 2,2-dimethyltrimethylene, 2,2-diethyltrimethylene, 1-methyltrimethylene, 2-methyltrimethylene, trimethylene, 2,2-di-n-propyltrimethylene, 1,1-dimethylethylene or 1-methylethylene. The position number of these substituents is based on either the order of N—R¹—S or that of S—R¹—N.

Examples of substituents of “optionally substituted alkylene” include alkylene (e.g., methylene, ethylene, trimethylene, tetramethylene, pentamethylene or the like), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like); alkoxy (e.g., methoxy, ethoxy or the like), alkylthio (e.g., methylthio, ethylthio or the like), alkylamino (e.g., methylamino, ethylamino, dimethylamino or the like), acylamino (e.g., acetylamino or the like), aryl (e.g., phenyl or the like), aryloxy(e.g., phenoxy or the like), halogen (fluoro, chloro, bromo, iodo), hydroxy, amino, nitro, alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl or the like), arylsulfonyl (e.g., benzenesulfonyl or the like), cyano, hydroxyamino, carboxy, alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl or the like), acyl (e.g., acetyl, benzoyl or the like), aralkyl (e.g., benzyl or the like), mercapto, hydorazino, amidino, guanidino or the like. One to four of these substituents may substitute at any position. Preferred as the substituent of “optionally substituted alkylene” is alkylene.

Alkylene substituted with alkylene include alkylene substituted via a spiro atom with alkylene (e.g., 2,2-ethylenetrimethylene, 2,2-trimethylenetrimethylene, 2,2-tetramethylenetrimethylene, 2,2-pentamethylenetrimethylene or the like) and alkylene substituted at the different positions with alkylene (e.g., 1,2-tetramethyleneethylene, 1,2-ethylenetrimethylene or the like). Preferred examples include 2,2-ethylenetrimethylene, 2,2-trimethylenetrimethylene, 2,2-tetramethylenetrimethylene, 2,2-pentamethylenetrimethylene, especially, 2,2-ethylenetrimethylene, 2,2-tetramethylenetrimethylene and 2,2-pentamethylenetrimethylene.

The term “alkyl” includes a C1-C10 straight or branched alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl, n-heptyl, n-octyl, n-noyl, n-decyl or the like. Preferred is a C1-C4 straight or branched alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and tert-butyl.

The term “alkoxy” includes an oxygen atom substituted with the above “alkyl”, for example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy or the like. Preferred is a C1-C4 straight or branched alkoxy, for example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and tert-butoxy.

The term “alkylthio” includes a sulfur atom substituted with the above “alkyl”, for example, methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, n-hexylthio or the like. Preferred is a C1-C4 straight or branched alkylthio, for example, methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, sec-butylthio and tert-butylthio.

Examples of substituents of “optionally substituted amino” includes alkyl (e.g., methyl, ethyl, n-propyl, i-propyl or the like), acyl (e.g., formyl, acetyl, propionyl, benzoyl or the like) or the like. A nitrogen atom of an amino group may be mono- or di-substituted with these substituents.

Examples of “optionally substituted amino” include amino, methylamino, ethylamino, n-propylamino, i-propylamino, dimethylamino, diethylamino, ethylmethylamino, acetylamino, N-acetylmethylamino, propylmethylamino or the like.

The term “aryl” includes a C6-C14 aromatic carbocyclic group, for example, phenyl, naphthyl, anthryl, phenanthryl or the like.

The term “aralkyl” includes the above “alkyl” substituted with the above “aryl”, for example, benzyl, phenylethyl (e.g., 1-phenylethyl, 2-phenylethyl), phenylpropyl (e.g., 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl or the like), naphthylmethyl (e.g., 1-naphthylmethyl, 2-naphthylmethyl or the like) or the like.

The term “aralkyloxy” includes an oxygen atom substituted with the above “aralkyl”, for example, benzyloxy, phenylethyloxy (e.g., 1-phenylethyloxy, 2-phenylethyloxy), phenylpropoxy (e.g., 1-phenylpropyloxy, 2-phenylpropyloxy, 3-phenylpropyloxy or the like), naphthylmethoxy (e.g., 1-naphthylmethoxy, 2-naphthylmethoxy or the like) or the like.

The term “aralkylthio” includes a sulfur atom substituted with the above “aralkyl”, for example, benzylthio, phenylethylthio (e.g., 11-phenylethylthio, 2-phenylethylthio), phenylpropylthio (e.g., 1-phenylpropylthio, 2-phenylpropylthio, 3-phenylpropylthio or the like), naphthylmethylthio (e.g., 1-naphthylmethylthio, 2-naphthylmethylthio or the like) or the like.

The term “aralkylamino” includes a nitrogen atom substituted with one or two of the above “aralkyl”, for example, benzylamino, phenylethylamino (e.g., 1-phenylethylamino, 2-phenylethylamino), phenylpropylamino (e.g., 1-phenylpropylamino, 2-phenylpropylamino, 3-phenylpropylamino), naphthylmethylamino (e.g., 1-naphthylmethylamino, 2-naphthylmethylamino or the like), dibenzylamino or the like.

The term “alkoxyalkyl” includes the above “alkyl” substituted with the above “alkoxy”, for example, methoxymethyl, ethoxymethyl, n-propoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-ethoxyethyl, 2-ethoxyethyl, 1-n-propoxyethyl, 2-n-propoxyethyl, 1-methoxy-n-propyl, 2-methoxy-n-propyl, 3-methoxy-n-propyl, 1-ethoxy-n-propyl, 2-ethoxy-n-propyl, 3-ethoxy-n-propyl, 1-n-propoxy-n-propyl, 2-n-propoxy-n-propyl, 3-n-propoxy-n-propyl or the like.

The term “alkylthioalkyl” includes the above “alkyl” substituted with the above “alkylthio”, for example, methylthiomethyl, ethylthiomethyl, n-propylthiomethyl, 1-methylthioethyl, 2-methylthioethyl, 1-ethylthioethyl, 2-ethylthioethyl, 1-n-propylthioethyl, 2-n-propylthioethyl, 3-n-propylthioethyl, 1-methylthio-n-propyl, 2-methylthio-n-propyl, 3-methylthio-n-propyl, 1-ethylthio-n-propyl, 2-ethylthio-n-propyl, 3-ethylthio-n-propyl, 1-n-propylthio-n-propyl, 2-n-propylthio-n-propyl, 3-n-propylthio-n-propyl or the like.

The term “optionally substituted aminoalkyl” includes the above “alkyl” substituted with the above “optionally substituted amino”, for example, N-methylaminomethyl, N-acetylaminomethyl, N,N-dimethylaminomethyl or the like.

The term “alkoxyalkoxy” includes the above “alkoxy” substituted with the above “alkoxy”, for example, methoxymethoxy, ethoxymethoxy, n-propoxymethoxy, isopropoxymethoxy, 1-methoxyethoxy, 2-methoxyethoxy or the like.

The term “alkylthioalkoxy” includes the above “alkoxy” substituted with the above “alkylthio”, for example, methylthiomethoxy, ethylthiomethoxy, n-propylthiomethoxy, isopropylthiomethoxy, 1-methylthioethoxy, 2-methoxyethoxy or the like.

The term “heteroaryl” includes a C1-C9 heteroaryl having one to four nitrogen atom(s), oxygen atom(s) and/or sulfur atom(s), for example, furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), furazanyl (e.g., 3-furazanyl), pyrazinyl (e.g., 2-pyrazinyl), oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl), benzofuryl (e.g., 2-benzo[b]furyl, 3-benzo[b]furyl, 4-benzo[b]furyl, 5-benzo[b]furyl, 6-benzo[b]furyl, 7-benzo[b]furyl), benzothienyl (e.g., 2-benzo[b]thienyl, 3-benzo[b]thienyl, 4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl, 7-benzo[b]thienyl), benzimidazolyl (e.g., 1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl), dibenzofuryl, benzoxazolyl, quinoxalinyl (e.g., 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl), cinnolinyl (e.g., 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), quinazolinyl (e.g., 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl), quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), phthalazinyl (e.g., 1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), puryl, pteridinyl (e.g., 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl), carbazolyl, phenanthridinyl, acridinyl (e.g., 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), isoindolyl, phenazinyl (e.g., 1-phenazinyl, 2-phenazinyl) or phenothiadinyl (e.g., 1-phenothiadinyl, 2-phenothiadinyl, 3-phenothiadinyl, 4-phenothiadinyl) or the like.

Preferred as heteroaryl of R³ and R⁴ is 3-pyridyl. Preferred as heteroaryl of R⁷ is 2-thienyl.

The ring A includes “optionally substituted aromatic carbocycle” or “optionally substituted aromatic heterocycle”.

The term “aromatic carbocycle” includes a C6-C14 aromatic carbocycle, for example, benzene, naphthalene, anthracene, phenanthrene or the like. Preferred is benzene or naphthalene.

The term “aromatic heterocycle” includes a C1-C9 aromatic ring having one to four nitrogen atom(s), oxygen atom(s) and/or sulfur atom(s), for example, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, oxazole, isoxazole, thiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrimidine, furazan, pyrazine, benzofuran, benzothiophene, benzimidazole, dibenzofuran, benzoxazole, quinoxaline, cinnoline, quinazoline, quinoline, phthalazine, isoquinoline, purine, pteridine, carbazole, phenanthridine, acridine, indole, isoindole or phenazine or the like. Preferred is pyridine, quinoline or isoquinoline.

Examples of the substituents of “optionally substituted aralkyloxy”, “optionally substituted aralkylthio”, “optionally substituted aralkylamino”, “optionally substituted aryl”, “optionally substituted heteroaryl”, “optionally substituted aryloxy”, “optionally substituted aromatic carbocycle”, “optionally substituted aromatic heterocycle” and “optionally substituted non-aromatic heterocyclic group” include alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, cycloalkyl, halogen, hydroxy, nitro, haloalkyl, haloalkoxy, optionally substituted carbamoyl, carboxy, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxyalkyl, alkylthioalkyl, optionally substituted aminoalkyl, alkoxyalkoxy, alkylthioalkoxy, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclic group, alkoxyiminoalkyl, a group of the formula: —C(═O)—R^(H) wherein R^(H) is hydrogen, alkyl, optionally substituted aryl or optionally substituted non-aromatic heterocyclic group, arylsulfonyl (e.g., benzenesulfonyl or the like), cyano, hydroxy amino, aralkyl (e.g., benzyl or the like), mercapto, hydrazino, amidino, guanidino, isocyano, isocyanato, thiocyanato, isothiocyanato, sulfamoyl, formyloxy, haloformyl, oxalo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino, azido, ureido, amidino, guanidino, oxo, thioxo or the like.

These substituents may substitute at any substitutable positions. Alkylenedioxy may substitute at the same or different positions on the ring. An example of alkylenedioxy includes —O—CH₂—O—, —O—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—O—.

The term “aryloxy” includes an oxygen atom substituted with the above “aryl”, for example, phenoxy, naphthoxy (e.g., 1-naphthoxy, 2-naphthoxy or the like), anthryloxy (e.g., 1-anthryloxy, 2-anthryloxy or the like), phenanthryl (e.g., 1-phenanthryl, 2-phenanthryl or the like) or the like.

The term “cycloalkyl” includes C3-C7 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like.

The term “halogen” includes fluoro, chloro, bromo and iodo. Preferred is fluoro, chloro or bromo.

The term “haloalkyl” includes the above “alkyl” substituted with one or more halogen, for example, chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, chloroethyl (e.g., 1-chloroethyl, 2-chloroethyl or the like), dichloroethyl (e.g., 1,1-dichloroethyl, 1,2-dichloroethyl, 2,2-dichloroethyl or the like) or the like.

The term “haloalkoxy” includes the above “alkoxy” substituted with one or more halogen, for example, dichloromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy (2,2,2-trifluoroethoxy or the like) or the like.

Examples of the substituents of “optionally substituted carbamoyl” include alkyl (e.g., methyl, ethyl, n-propyl, i-propyl or the like), acyl (e.g., formyl, acetyl, propionyl, benzoyl or the like) or the like. The nitrogen atom of carbamoyl group may be mono- or di-substituted with these substituents.

Preferred as “optionally substituted carbamoyl” is carbamoyl, N-methylcarbamoyl or N-ethylcarbamoyl.

The term “alkoxycarbonyl” includes carbonyl substituted with “alkoxy”. Preferred is methoxycarbonyl, ethoxycarbonyl or the like.

The term “alkylsulfinyl” includes sulfinyl substituted with the above “alkyl”. Preferred is methanesulfinyl, ethanesulfinyl or the like.

The term “alkylsulfonyl” includes sulfonyl substituted with the above “alkyl”. Preferred is methanesulfonyl, ethanesulfonyl or the like.

The term “non-aromatic heterocyclic group” includes a C1-C9 non-aromatic ring having one to four nitrogen atom(s), oxygen atom(s) and/or sulfur atom(s), for example, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidino, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, piperazino, 2-piperazinyl, 2-morpholinyl, 3-morpholinyl, morpholino, tetrahydropyranyl or the like. Preferred is morpholino, pyrrolidino, piperidino or piperazino.

The term “alkoxyiminoalkyl” include the above “alkyl” substituted with alkoxyimino, for example, methoxyiminomethyl, ethoxyiminomethyl, 1-methoxyiminoethyl or the like.

Examples of a group of the formula: —C(═O)—R^(H) wherein R^(H) is hydrogen, alkyl, optionally substituted aryl or optionally substituted non-aromatic heterocyclic group include formyl, acetyl, benzoyl, toluoyl, morpholinocarbonyl or the like.

The term “m” is an integer of 0 to 2. Preferred as “m” is 0.

The term “an agonistic activity to a cannabinoid type 2 receptor” includes agonizing a cannabinoid type 2 receptor.

The compounds of the present invention can be prepared in accordance with the following processes.

wherein R¹ is optionally substituted alkylene, R² is alkyl; a group of the formula: —C(═R⁵)—R⁶ wherein R⁵ is O or S, R⁶ is alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aralkyloxy, optionally substituted aralkylthio, optionally substituted aralkylamino, alkoxyalkyl, alkylthioalkyl or optionally substituted aminoalkyl; or a group of the formula: —SO₂R⁷ wherein R⁷ is alkyl, optionally substituted amino, optionally substituted aryl or optionally substituted heteroaryl, R³ and R⁴ each is independently hydrogen, alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, cycloalkyl, halogen, hydroxy, nitro, haloalkyl, haloalkoxy, optionally substituted carbamoyl, carboxy, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxyalkyl, alkylthioalkyl, optionally substituted aminoalkyl, alkoxyalkoxy, alkylthioalkoxy, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclic group, alkoxyiminoalkyl, or a group of the formula: —C(═O)—R^(H) wherein R^(H) is hydrogen, alkyl, optionally substituted aryl or optionally substituted non-aromatic heterocyclic group, or R³ and R⁴ taken together may form —O—CH₂—O—, m is an integer of 0 to 2, A is optionally substituted aromatic carbocycle or optionally substituted aromatic heterocycle. Process 1

This is a process for producing a compound of the formula (IV) which comprises converting amino group of a compound of the formula (III) to isothiocyanic acid ester (isothiocyanate).

A method for converting amino group to isothio cyanic acid ester (isothiocyanate) includes the following methods; 1) a method which comprises reacting the starting compound with carbon disulfide in the presence of a base such as ammonia (NH₃, NH₄OH), triethylamine (Et₃N) and reacting, the obtained dithiocarbamate with ethyl chlorocarboxylate (ClCO₂Et) and triethylamine (Et₃N), 2) a method which comprises reacting the above dithiocarbamate with acid metalate such as lead nitrate or the like, 3) a method of reacting thiophosgene (CSCl₂) and 4) a method of reacting thiocarbonyldiimidazole or the like.

In the above 1), a base (1.0 to 1.5 mole equivalent) and carbon disulfide (1.0 to 1.5 mole equivalent) are added to a solution of a compound of the formula (III) in an aprotic solvent (e.g., diethylether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform or the like) and the mixture is stirred for 0.5 to 10 hours. After that, ethyl chlorocarboxylate (1.0 to 1.5 mole equivalent) and triethylamine (1.0 to 1.5 mole equivalent) are added thereto and the mixture is stirred in the same solvent for 0.5 to 10 hours. The reaction temperature is preferably 0 to 100° C., especially 0° C. to room temperature.

In the above 3), thiophosgene (1.0 to 1.5 mole equivalent) is added to a solution of the compound of the formula (III) in an aprotic solvent (e.g., diethylether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform or the like) and stirred for 0.5 to 10 hours. The reaction temperature is preferably 0 to 100° C., especially 0° C. to room temperature.

In the above 4), thiocarbonyldiimidazole (1.0 to 1.5 mole equivalent) is added to a solution of the compound of the formula (III) in an aprotic solvent (e.g., diethylether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform or the like) and stirred for 0.5 to 10 hours. The reaction temperature is preferably 0 to 100° C., especially 0° C. to room temperature.

Examples of the compound of the formula (III) wherein m is 0 include aniline, 2-methylaniline, 2-ethylaniline, 2-n-propylaniline, 2-i-propylaniline, 2-n-butylaniline, 2-sec-butylaniline, 2-t-butylaniline, 3-methylaniline, 3-i -propylaniline, 3-i-propyl-4-methylaniline, 3-t-butylaniline, 4-methylaniline, 4-i-propylaniline, 2,6-dimethylaniline, 2,3-dimethylaniline, 2,4-dimethylaniline, 3,4-diethylaniline, 2,5-dimethylaniline, 3,4-dimethylaniline, 3,5-dimethylaniline, 2,6-diethylaniline, 2,6-di-i-propylaniline, 2-methoxyaniline, 2-ethoxyaniline, 2-i-propoxyaniline, 3-methoxyaniline, 3,5-dimethoxyaniline, 3-n-butoxyaniline, 4-n-butoxyaniline, 4-ethoxyaniline, 3,4-dimethoxyaniline, 2-methylthioaniline, 2-ethylthioaniline, 2-i -propylthioaniline, 2-N,N-dimethylaminoaniline, 2-phenylaniline, 3-phenylaniline, 4-phenoxyaniline, 2-cyclohexylaniline, 2-cyclopentylaniline, 2-nitroaniline, 2,4-dinitroaniline, 2-fluoroaniline, 2-chloroaniline, 4-chloroaniline, 2,3-dichloroaniline, 3,4-dichloroaniline, 2-i-propyl-4-nitroaniline, 2-i-propyl-6-nitroaniline, 2-hydroxyaniline, 2-N,N-dimethylaminocarbonylaniline, 2-N-acetylaniline, 2-(1-ethylpropyl)aniline, 2-i-propyl-4-methylaniline, 2-i-propyl-4-hydroxyaniline, 2-i-propyl-4-chloroaniline, 2-i-propyl-4-aminoaniline, 2-i-propyl-5-methylaniline, 2-i -propyl-5-hydroxy aniline, 2-i-propyl-5-chloroaniline, 4-chloro-3-methylaniline, 3,4-methylenedioxyaniline or the like.

Examples of the compound of the formula (III) wherein in is 1 include benzylamine, 2-methylbenzylamine, 2-ethylbenzylamine, 2-n-propylbenzylamine, 2-i-propylbenzylamine, 2-n-butylbenzylamine, 2-sec-butylbenzylamine, 2-t-butylbenzylamine, 3-methylbenzylamine, 3-i -propylbenzylamine, 3-i-propyl-4-methylbenzylamine, 3-t-butylbenzylamine, 4-methylbenzylamine, 4-i-propylbenzylamine, 2,6-dimethylbenzylamine, 2,3-dimethylbenzylamine, 2,4-dimethylbenzylamine, 3,4-diethylbenzylamine, 2,5-dimethylbenzylamine, 3,4-dimethylbenzylamine, 3,5-dimethylbenzylamine, 2,6-diethylbenzylamine, 2,6-di-i-propylbenzylamine, 2-methoxybenzylamine, 2-ethoxybenzylamine, 2-i-propoxybenzylamine, 3-methoxybenzylamine, 3,5-dimethoxybenzylamine, 3-n-butoxybenzylamine, 4-n-butoxybenzylamine, 4-ethoxybenzylamine, 3,4-dimethoxybenzylamine, 2-methylthiobenzylamine, 2-ethylthiobenzylamine, 2-i-propylthiobenzylamine, 2-N,N-dimethylaminobenzylamine, 2-phenylbenzylamine, 3-phenylbenzylamine, 4-phenoxybenzylamine, 2-cyclohexylbenzylamine, 2-cyclopentylbenzylamine, 2-nitrobenzylamine, 2,4-dinitrobenzylamine, 2-fluorobenzylamine, 2-chlorobenzylamine, 4-chlorobenzylamine, 2,3-dichlorobenzylamine, 3,4-dichlorobenzylamine, 2-i-propyl-4-nitrobenzylamine, 2-i-propyl-6-nitrobenzylamine, 2-hydroxybenzylamine, 2-N,N-dimethylaminocarbonylbenzylamine, 2-N-acetylbenzylamine, 2-(1-ethylpropyl)benzylamine, 2-i-propyl-4-methylbenzylamine, 2-i-propyl-4-hydroxybenzylamine, 2-i-propyl-4-chlorobenzylamine, 2-i-propyl-4-aminobenzylamine, 2-i-propyl-5-methylbenzylamine, 2-i-propyl-5-hydroxybenzylamine, 2-i-propyl-5-chlorobenzylamine, 4-chloro-3-methylbenzylamine, 3,4-methylenedioxybenzylamine or the like.

Examples of the compound of the formula (III) wherein in is 2 include phenethylamine, 2-methylphenethylamine, 2-ethylphenethylamine, 2-n-propylphenethylamine, 2-i-propylphenethylamine, 2-n-butylphenethylamine, 2-sec-butylphenethylamine, 2-t-butylphenethylamine, 3-methylphenethylamine, 3-i-propylphenethylamine, 3-i-propyl-4-methylphenethylamine, 3-t-butylphenethylamine, 4-methylphenethylamine, 4-i-propylphenethylamine, 2,6-dimethylphenethylamine, 2,3-dimethylphenethylamine, 2,4-dimethylphenethylamine, 3,4-diethylphenethylamine, 2,5-dimethylphenethylamine, 3,4-dimethylphenethylamine, 3,5-dimethylphenethylamine, 2,6-diethylphenethylamine, 2,6-di-i-propylphenethylamine, 2-methoxyphenethylamine, 2-ethoxyphenethylamine, 2-i -propoxyphenethylamine, 3-methoxyphenethylamine, 3,5-dimethoxyphenethylamine, 3-n-butoxyphenethylamine, 4-n-butoxyphenethylamine, 4-ethoxyphenethylamine, 3,4-dimethoxyphenethylamine, 2-methylthiophenethylamine, 2-ethylthiophenethylamine, 2-i-propylthiophenethylamine, 2-N,N-dimethylaminophenethylamine, 2-phenylphenethylamine, 3-phenylphenethylamine, 4-phenoxyphenethylamine, 2-cyclohexylphenethylamine, 2-cyclopentylphenethylamine, 2-nitrophenethylamine, 2,4-dinitrophenethylamine, 2-fluorophenethylamine, 2-chlorophenethylamine, 4-chlorophenethylamine, 2,3-dichlorophenethylamine, 3,4-dichlorophenethylamine, 2-i-propyl-4-nitrophenethylamine, 2-i-propyl-6-nitrophenethylamine, 2-hydroxyphenethylamine, 2-N,N-dimethylaminocarbonylphenethylamine, 2-N-acetylphenethylamine, 2-(1-ethylpropyl)phenethylamine, 2-i-propyl-4-methylphenethylamine, 2-i-propyl-4-hydroxyphenethylamine, 2-i-propyl-4-chlorophenethylamine, 2-i-propyl-4-aminophenethylamine, 2-i-propyl-5-methylphenethylamine, 2-i-propyl-5-hydroxyphenethylamine, 2-i-propyl-5-chlorophenethylamine, 4-chloro-3-methylphenethylamine, 3,4-methylenedioxyphenethylamine or the like.

Process 2

This is a process for producing a compound of the formula (V) which comprises reacting an isothiocyanate of the compound of the formula (IV) with NH₂—R¹—OH.

This process can be carried out in an aprotic solvent (e.g., diethylether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform or the like).

The reaction temperature is preferably 0 to 100° C., especially 0° C. to room temperature. The reaction time is 0.5 to 10 hours.

The amount of NH₂—R¹—OH wherein R¹ is optionally substituted alkylene is 1.0 to 1.5 mole equivalent to that of the compound of the formula (IV).

Examples of NH₂—R¹—OH include 2-aminoethanol, 2-amino-2-methylethanol, 2-amino-1-methylethanol, 2-amino-1,1-dimethylethanol, 3-aminopropanol, 3-amino-2,2-dimethylpropanol, 3-amino-1-methylpropanol, 3-amino-2-methylpropanol, 3-amino-3-methylpropanol, 3-amino-2,2-diethylpropanol, 1-aminomethyl-1-hydroxymethylcyclopropane, 1-aminomethyl-1-(hydroxymethyl)cyclobutane, 2-(aminomethyl)cyclopentanol or the like.

Process 3

This is a process for producing a compound of the formula (VI) which comprises the cyclization of the compound of the formula (V).

A method of the cyclization includes 1) a method which comprises reacting with diethylazodicarboxylate (DEAD) and triphenylphosphine (Ph₃P), 2) a method which comprises reacting with hydrochloric acid or the like.

In the above 1), the reaction can be carried out in an aprotic solvent (e.g., diethylether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform or the like) with stirring for 0.5 to 5 hours at 0° C. to room temperature. The amount of diethylazodicarboxylate (DEAD) and triphenylphosphine (Ph₃P) are 1.0 to 1.5 mole equivalent to that of the compound (V).

In the above 2), the reaction can be carried out in concentrated hydrochloric acid with refluxing for 0.5 to 10 hours.

Process 4

This is a process for producing a compound of the formula (II) which comprises introducing R² (a group of the formula: —C(═R⁵)—R⁶ or a group of the formula: —SO₂R⁷ wherein R⁵ is O or S, R⁶ is alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aralkyloxy, optionally substituted aralkylthio, optionally substituted aralkylamino, alkoxyalkyl, alkylthioalkyl or optionally substituted aminoalkyl, R⁷ is alkyl, optionally substituted amino, optionally substituted aryl or optionally substituted heteroaryl, to the compound of the formula (VI).

This process can be carried out by reacting with a compound of the formula: X—C(═R⁵)—R⁶ wherein R⁵ and R⁶ are as defined above and X is halogen in the presence of a base (e.g., triethylamine, pyridine, N,N-dimethylaminopyridine or the like). This process can be carried out under generally known conditions of N-acylation. For example, the reaction can be carried out in an aprotic solvent (e.g., diethylether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform or the like) with stirring at 0 to 100° C. for 0.5 to 10 hours.

A thioic acid ester, a compound wherein R⁵ is S, R⁶ is alkylthio or optionally substituted aralkylthio can be prepared by reacting with carbon dioxide (CS₂) in the presence of a base (e.g., sodium hydride or the like), and reacting with halogenated alkyl (e.g., methyl iodide, ethyl iodide or the like) or halogenated aralkyl (e.g., benzylbromide or the like). The reaction can be carried out in an aprotic solvent (e.g., diethylether, tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane, chloroform or the like) with stirring at 0° C. to room temperature.

When R² to be introduced is a group of the formula: —SO₂R⁷ wherein R⁷ is alkyl, optionally substituted amino, optionally substituted aryl or optionally substituted heteroaryl, the compound of the formula (VI) can be reacted with a compound of the formula: R⁷SO₂X wherein X is halogen or the like in the presence of a base.

A prodrug is a derivative which is converted to a pharmaceutically active compound of the present invention under a physiological condition. Method for the selection and process of an appropriate prodrug derivative are described in the literature such as Design of Prodrugs, Elsevier, Amsterdam 1985.

A prodrug of the present invention can be prepared by introducing a leaving group to substituents on ring A which are substitutable (e.g., amino, hydroxy or the like). Examples of a prodrug derived form a compound having an amino group includes carbamate derivatives (e.g., methylcarbamate, cyclopropylmethylcarbamate, t-butylcarbamate, benzylcarbamate or the like), amide derivatives (e.g., formamide, acetamide or the like), N-alkyl derivative (e.g., N-allylamine, N-methoxymethylamine or the like) or the like. Examples of a prodrug derived form a compound having hydroxy group include ether derivatives (methoxymethylether, methoxyethoxymethylether or the like), ester derivatives (e.g., acetate, pivaloate, benzoate or the like) or the like.

Examples of a pharmaceutically acceptable salt include basic salts (e.g., alkali metal salts such as sodium or potassium salts; alkaline-earth metal salts such as calcium or magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine or procaine salts; aralkyl amine salts such as N,N-dibenzylethylenediamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts or lysine salts). Acid addition salts include, for example, mineral acid salts such as hydrochlorides salts, sulfates salts, nitrate salts, phosphates salts, carbonates salts, hydrogen carbonates salts or perchlorates salts; organic acid salts such as acetates, propionates, lactates, maleates, fumarates, tartrates, malates, succinates, or ascorbates; sulfonates such as methanesulfonates, isethionates, benzenesulfonates, or p-toluenesulfonates; and acidic amino acid salts such as aspartates or glutamates.

A solvate includes a solvate of the compound of the formula (I) or (II), a prodrug of itself or a pharmaceutically acceptable salt thereof, for example, monosolvate, disolvate, monohydrate, dihydrate or the like.

The compound of the present invention has a binding activity to the cannabinoid type 2 receptor (CB2R), and selectively binds to the cannabinoid type 2 receptor (CB2R) to exhibit an antagonistic activity or agonistic activity to CB2R, especially an agonistic activity to CB2R.

Since the compound of the present invention does not have a binding activity to the cannabinoid type 1 receptor (CB1R), the present compound neither causes side effects on the central nervous system such as illusion or the drug dependence associated with the cannabinoid type 1 receptor.

Therefore, the compound of the present invention can be used for treating or preventing diseases associated with the cannabinoid type 2 receptor (CB2R). For example, Proc. Natl. Acad. Sci. USA 96, 14228-14233. discloses that CB2R agonists have an anti-inflammatory activity and analgesic activity. Nature, 1998, 349, 277-281 discloses that CB2R agonists have an analgesic activity. European Journal of Pharmacology 396 (2000) 85-92 discloses that CB2R antagonists have an analgesic activity.

The compound of the present invention suppresses an activation of cells in immunocyte or phlogocyte to exhibit an activity to the peripheral cell system (e.g., an immunosuppressive activity, an anti-inflammatory activity and an analgesic activity). Thus, the present compounds can be used as anti-inflammatory agents, antiallergenic agents, analgesic agents, immune deficiency treating agents, immunosuppressive agents, immunomodulating agents, autoimmune disease treating agents, chronic rheumatoid arthritis treating agents, multiple sclerosis treating agents or the like.

Agonists to the cannabinoid type 2 receptor are known to suppress nephritis caused by rat Thy-1 antibody in WO97/29079. Therefore, the present compounds are useful as nephritis treating agents.

When using a compound of the present invention in treatment, it can be formulated into ordinary formulations for oral and parenteral administration. A pharmaceutical composition containing a compound of the present invention can be in the form for oral and parenteral administration. Specifically, it can be formulated into formulations for oral administration such as tablets, capsules, granules, powders, syrup, and the like; those for parenteral administration such as injectable solution or suspension for intravenous, intramuscular or subcutaneous injection, inhalant, eye drops, nasal drops, suppositories, or percutaneous formulations such as ointment.

In preparing the formulations, carriers, excipients, solvents and bases known to one ordinary skilled in the art may be used. Tablets are prepared by compressing or formulating an active ingredient together with auxiliary components. Examples of usable auxiliary components include pharmaceutically acceptable excipients such as binders (e.g., cornstarch), fillers (e.g., lactose, microcrystalline cellulose), disintegrates (e.g., starch sodium glycolate) or lubricants (e.g., magnesium stearate). Tablets may be coated appropriately. In the case of liquid formulations such as syrups, solutions or suspensions, they may contain suspending agents (e.g., methyl cellulose), emulsifiers (e.g., lecithin), preservatives and the like. In the case of injectable formulations, it may be in the form of solution or suspension, or oily or aqueous emulsion, which may contain suspension-stabilizing agent or dispensing agent, and the like. In the case of an inhalant, it is formulated into a liquid formulation applicable to an inhaler. In the case of eye drops, it is formulated into a solution or a suspension.

Although an appropriate dosage of the present compound varies depending on the administration route, age, body weight, sex, or conditions of the patient, and the kind of drug(s) used together, if any, and should be determined by the physician in the end, in the case of oral administration, the daily dosage can generally be between about 0.01-100 mg, preferably about 0.01-10 mg, more preferably about 0.01-1 mg, per kg body weight. In the case of parenteral administration, the daily dosage can generally be between about 0.001-100 mg, preferably about 0.001-1 mg, more preferably about 0.001-0.1 mg, per kg body weight. The daily dosage can be administered in 1-4 divisions.

EXAMPLE

The following Examples are provided to further illustrate the present invention and are not to be construed as limiting the scope.

The meaning of each abbreviation are shown as follows.

Me: methyl, Et: ethyl, Pr: propyl, Pr^(i): i-propyl,

Bu: butyl, Bu^(i): i-butyl, Bu^(s): sec-butyl,

Bu^(t): t-butyl

Ph: phenyl, Ac: acetyl, Bn: benzyl

DMF: N,N-dimethylformamide, THF: tetrahydrofuran,

DEAD: diethyl azodicarboxylate,

Reference Example 1-1 Preparation of (2-isopropylphenyl)isothiocyanate (Compound 2)

To a mixture of 2-isopropylaniline (5.00 g), triethylamine (3.74 g) and toluene (10 ml) was added dropwise for 10 minutes carbon dioxide (2.81 g). The mixture was stirred at room temperature for 1 hour and kept stationary for 12 hours. The reaction mixture was concentrated under reduced pressure. Dichloromethane (20 ml) and triethylamine (3.74 g) were added thereto. To the solution was added under ice-cooling for 10 minutes ethyl chlorocarbonate (4.01 g). The mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 10% hydrochloric acid (20 ml). The mixture was extracted with dichloromethane (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (2-isopropylphenyl)isothiocyanate (6.55 g, yield: 99%) as yellow oil.

¹H-NMR (δ ppm TMS/CDCl₃) 1.25(6H, d, J=6.7), 3.25(1H, q, J=6.7), 7.14-7.30(4H, m).

Reference Example 1-2 Preparation of (2-isopropylphenyl)isothiocyanate (Compound 2)

To a solution of 2-isopropylaniline (1.81 g) in diethylether (20 ml) was added dropwise under ice-cooling for 10 minutes thiophosgene (1.54 g). The mixture was stirred at room temperature for 1 hour.

To the reaction solution was added water (30 ml). The mixture was extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (2-isopropylphenyl)isothiocyanate (2.35 g, yield: 99%) as brown oil.

Reference Example 2 Preparation of N-(2-isopropylphenyl)-N′-(1-hydroxy-2,2-dimethyl)propylthiourea (Compound 3)

To a solution of (2-isopropylphenyl)isothiocyanate (3.30 g) in diethylether (20 ml) was added 3-amino-2,2-dimethylpropanol (1.92 g). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give N-(2-isopropylphenyl)-N′-(1-hydroxy-2,2-dimethyl)propylthiourea (4.60 g, yield: 88%) as yellow oil.

¹H-NMR (δ ppm TMS/CDCl₃) 0.82(6H, s), 1.25(6H, d, J=6.7), 3.11(1H, q, J=6.7), 3.25(2H, s), 3.55(2H, d, J=6.3), 6.05(1H, m), 7.17-7.40(4H, m).

Reference Example 3 Preparation of 2-(2-isopropylphenyl)imino-5,5 dimethyl-1,3-thiazine (Compound 4)

To N-(2-isopropylphenyl)-N′-(1-hydroxy-2,2-dimethyl)propylthiourea (10.37 g) was added concentrated hydrochloric acid (5 ml). The mixture was refluxed for 3 hours. The reaction solution was cooled to room temperature and poured into an aqueous solution of 20% sodium hydroxide (25 ml). The precipitated crystal was filtered and recrystallized with ethyl acetate to give 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (4.80 g, yield: 50%) as a white crystal.

M.p. 155-157° C.

¹H-NMR (δ ppm TMS/CDCl₃) 1.15(6H, s), 1.20(6H, d, J=6.7), 2.67(2H, s), 3.09(2H, s), 3.15.(1H, q, J=6.7), 6.88(1H, m), 7.05-7.11(2H, m), 7.20(1H, m)

Reference Example 4 Preparation of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (Compound 4)

To a solution of N-(2-isopropylphenyl)-N′-(1-hydroxy-2,2-dimethyl)propylthiourea (1.00 g) in tetrahydrofuran (6 ml) was added dropwise thionylchloride (0.60 g). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. To the solution were added acetonitrile (20 ml) and potassium carbonate (0.93 g). The mixture was refluxed for 2 hours. To the solution was added water (40 ml). The mixture was extracted with dichloromethane (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.45 g, yield: 48%) as a white crystal.

The following Examples 1 to 5 were carried out by using 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine prepared in Reference Example 3 and 4.

Example 1 Preparation of 3-ethyl-2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (Compound I-1)

To a solution of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.26 g) in N,N-dimethylformamide (2 ml) was added under ice-cooling 60% sodium hydride (0.05 g). The mixture was stirred for 30 minutes. Ethyliodide (0.17 g) was added thereto. The mixture was stirred at room temperature for 2 hours. To a reaction mixture was added water (30 ml), extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 3-ethyl-2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.21 g, yield: 71%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃) 1.13 (6H, s), 1.20 (6H, d, J=6.9), 1.25 (3H, t, J=7.4), 2.61 (2H, s), 3.05 (2H,s), 3.17 (1H, m), 3.64 (2H, q, J=6.9), 6.72-6.80 (1H, m), 6.98-7.07 (2H, m), 7.20-7.32 (1H, m).

Example 2 Preparation of 2-(2-isopropylphenyl)imino-3-propionyl-5,5-dimethyl-1,3-thiazine (Compound I-2)

To a mixture of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.26 g), triethylamine (0.15 g) and dichloromethane (5 ml) was added dropwise for 5 minutes propionylchloride (0.13 g). The mixture was stirred at room temperature for 2 hours. To the solution was added water (30 ml). The mixture was extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2-(2-isopropylphenyl)imino-3-propionyl-5,5-dimethyl-1,3-thiazine (0.18 g, yield: 56%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃)1.14 (6H, s), 1.20 (6H, d, J=6.9), 1.22 (3H, t, J=7.4), 2.60 (2H, s), 2.95 (2H, q, J=7.4), 2.96 (1H, q, J=6.9), 3.73 (2H, s), 6.73-6.78 (1H, m), 7.10-7.17 (2H, m), 7.25-7.32 (1H, m).

Example 3 Preparation of 3-(ethoxycarbonyl)-2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (Compound I-3)

To a mixture of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.26 g), triethylamine (0.15 g) and dichloromethane (5 ml) was added dropwise for 5 minutes ethyl chlorocarbonate (0.13 g). The mixture was stirred at room temperature for 2 hours. To the solution was added water (30 ml). The mixture was extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 3-(ethoxycarbonyl)-2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.23 g, yield: 68%) as a white crystal. M.p. 84-86° C.

¹H-NMR (δ ppm TMS/CDCl₃) 1.16 (6H, s), 1.21 (6H, d, J=6.9), 1.36 (3H, t, J=7.1), 2.59 (2H, s), 3.17 (1H, q, J=6.9), 3.65 (2H, s), 4.32 (2H, q, J=7.1), 6.74-6.78 (1H,m), 7.12-7.16 (2H, m), 7.30-7.36 (1H, m).

Example 4 Preparation of 3-(ethylthiocarbonyl)-2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (Compound I-4).

To a mixture of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (1.00 g), triethylamine (0.58 g) and dichloromethane (5 ml) was added dropwise for 5 minutes ethyl chlorothiocarbonate (0.56 g). The mixture was stirred at room temperature for 1 hour. To the solution was added water (30 ml). The mixture was extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 3-(ethylthiocarbonyl)-2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.74 g, yield: 56%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃)1.16 (6H, s), 1.21 (6H, d, J=6.9), 1.36 (3H, t, J=7.1), 2.63 (2H, s), 2.89 (2H, q, J=7.1), 3.15 (1H, q, J=6.9), 3.77 (2H, s), 6.79-6.85 (1H,m), 7.12-7.16 (2H, m), 7.30-7.36 (1H, m).

Example 5 Preparation of 2-(2-isopropylphenyl)imino-3-(methylthio)thiocarbonyl-5,5-dimethyl-1,3-thiazine (Compound I-5)

To a mixture of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.26 g), carbon dioxide (0.09 g) and N,N-dimethylformamide (2 ml) was added under ice-cooling 60% sodium hydride (0.05 g). The mixture was stirred for 30 minutes. Methyliodide (0.17 g) was added thereto. The mixture was stirred at room temperature for 2 hours. To the solution was added water (30 ml), extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2-(2-isopropylphenyl)imino-3-(methylthio)thiocarbonyl-5,5-dimethyl-1,3-thiazine (0.14 g, yield: 40%) as a yellow crystal. M.p. 77-79° C.

¹H-NMR (δ ppm TMS/CDCl₃)1.20 (6H, d, J=6.9), 1.23 (6H, s), 2.65 (3H, s), 2.68 (2H, s), 3.11 (1H, q, J=6.9), 4.51 (2H, s), 6.83-6.90 (1H, m), 7.11-7.18 (2H, m), 7.28-7.35 (1H, m).

The following Reference Example 5 was carried out in accordance with Reference Example 2 and 3.

Reference Example 5 Preparation of 2-(2-isopropylphenyl)imino-1,3-thiazolidine (Compound 6)

To a solution of (2-isopropylphenyl)isothiocyanate (2.00 g) in diethylether (20 ml) was added 2-aminoethanol (0.69 g). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. To the obtained oil was added concentrated hydrochloric acid (5 ml). The mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature and poured into an aqueous solution of 20% sodium hydroxide (25 ml). The mixture was extracted with dichloromethane (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2-(2-isopropylphenyl)imino-1,3-thiazolidine (1.80 g, yield: 73%) as a white crystal. M.p. 76-77° C.

¹H-NMR (δ ppm TMS/CDCl₃) 1.20(6H, d, J=6.7), 3.15(1H, q, J=6.7), 3.27(2H, t, J=6.7), 3.67(2H, t, J=6.7), 6.95-6.99(1H, m), 7.05-7.19(2H, m), 7.22-7.26(1H, m).

The following Example 6 and 7 were carried out by using 2-(2-isopropylphenyl)imino-1,3-thiazolidine prepared in Reference Example 5.

Example 6 Preparation of 3-(ethylthiocarbonyl)-2-(2-isopropylphenyl)imino-1,3-thiazolidine (Compound I-6)

To a mixture of 2-(2-isopropylphenyl)imino-1,3-thiazolidine (0.25 g), triethylamine (0.15 g) and dichloromethane (5 ml) was added dropwise for 5 minutes ethyl clhlorothiocarboxylate (0.15 g). The mixture was stirred for 2 hours. To the solution was added water (30 ml). The mixture was extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 3-(ethylthiocarbonyl)-2-(2-isopropylphenyl)imino-1,3-thiazolidine (0.27 g, yield: 77%) as a white crystal. M.p. 79-81° C.

¹H-NMR (δ ppm TMS/CDCl₃) 1.20 (6H, d, J=6.9), 1.30 (3H, t, J=7.4), 2.90 (2H, t, J=7.4), 3.15 (2H, t, J=7.4), 3.20 (1H, q, J=6.9), 4.31 (2H, t, J=7.4), 6.79-6.82 (1H, m), 7.07-7.16 (2H, m), 7.28-7.32 (1H, m).

Example 7 Preparation of 2-(2-isopropylphenyl)imino-3-(methylthio)thiocarbonyl-1,3-thiazolidine (Compound I-7)

To a mixture of 2-(2-isopropylphenyl)imino-1,3-thiazolidine (0.22 g), carbon disulfide (0.09 g) and N,N-dimethylformamide (2 ml) was added under ice-cooling 60% sodium hydride (0.05 g). The mixture was stirred for 30 minutes. Methyliodide (0.17 g) was added thereto. The mixture was stirred at room temperature for 2 hours. To the mixture was added water (30 ml). The mixture was extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2-(2-isopropylphenyl)imino-3-(methylthio)thiocarbonyl-1,3-thiazolidine (0.14 g, yield: 45%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃) 1.23 (6H, d, J=6.9), 2.65 (3H, s), 2.90 (2H, t, J=7.4), 3.20 (1H, q, J=6.9), 4.45 (2H, t, J=7.4), 6.79-6.82 (1H, m), 7.07-7.16 (2H, m), 7.28-7.32 (1H, m).

Reference Example 6 Preparation of (2-methoxybenzyl)isothiocyanate (Compound 8)

To a solution of 2-methoxybenzylamine (1.80 g) in diethylether (20 ml) was added dropwise under ice-cooling for 10 minutes thiophosgene (1.54 g). The mixture was stirred at room temperature for 1 hour. To the reaction solution was added water (30 ml), extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (2-methoxybenzyl)isothiocyanate (2.35 g, yield: 99%) as brown oil.

¹H-NMR (δ ppm TMS/CDCl₃) 3.86(3H, s), 4.70(2H, s), 6.88 (1H, d, J=7.4), 6.98(1H, t, J=7.4), 7.24-7.30(2H, m).

Reference Example 7 Preparation of N-(2-methoxybenzyl)-N′-(1-hydroxy-2,2-dimethyl)propylthiourea (Compound 9)

To a solution of (2-methoxybenzyl)isothiocyanate (2.35 g) in diethylether (20 ml) was added 3-amino-2,2-dimethylpropanol (1.34 g). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give N-(2-methoxybenzyl)-N′-(1-hydroxy-2,2-dimethyl)propylthiourea (3.70 g, yield: 99%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃) 0.82(6H, s), 3.25(2H, s), 3.55(2H, d, J=6.3), 3.86(3H, s), 4.70(2H, s), 6.50(1H, brs), 6.88(1H, d, J=7.4), 6.95(1H, t, J=7.4), 7.24-7.30(2H, m).

Reference Example 8 Preparation of 2-(2-methoxybenzyl)imino-5,5-dimethyl-1,3-thiazine (Compound 10)

To a mixture of N-(2-methoxybenzyl)-N′-(1-hydroxy-2,2-dimethyl)propylthiourea (3.70 g), triphenylphosphine (3.44 g) and tetrahydrofuran (20 ml) was added dropwise for 10 minutes diethyl azodicarboxylate (2.28 g). The mixture was stirred at room temperature for 2 hours. To the solution was added water (40 ml). The mixture was extracted with dichloromethane (90 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2-(2-methoxybenzyl)imino-5,5-dimethyl-1,3-thiazine (0.87 g, yield: 25%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃) 1.05(6H, s,), 2.75(2H, s), 3.23(2H, s), 3.83(3H, s), 4.41(2H, s), 6.86-6.95(1H, m), 7.20-7.30(1H, m), 7.44-7.48 (2H, m).

The following Examples 8 and 9 were carried out by using 2-(2-methoxybenzyl)imino-5,5-dimethyl-1,3-thiazine prepared in Reference Example 8.

Example 8 Preparation of 3-(ethylthiocarbonyl)-2-(2-methoxybenzyl)imino-5,5-dimethyl-1,3-thiazine (Compound I-8)

To a mixture of 2-(2-methoxybenzyl)imino-5,5-dimethyl-1,3-thiazine (0.28 g), triethylamine (0.15 g) and dichloromethane (5 ml) was added dropwise for 5 minutes ethyl chlorothiocarboxylate (0.17 g). The mixture was stirred at room temperature for 1 hour. To the reaction solution was added water (30 ml), extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 3-(ethylthiocarbonyl)-2-(2-methoxybenzyl)imino-5,5-dimethyl-1,3-thiazine (0.20 g, yield: 57%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃) 1.15 (6H, s), 1.25 (3H, t, J=7.4), 2.69 (2H, s), 2.83 (2H, q, J=7.4), 3.69 (2H, s), 3.84 (3H, s), 4.61 (2H, s), 6.86 (1H, d, J=8.2), 6.96 (1H, t, J=8.2), 7.26 (1H, t, J=8.2), 7.55 (1H, t, J=8.2).

Example 9 Preparation of 2-(2-methoxybenzyl)imino-3-(methylthio)thiocarbonyl-5,5-dimethyl-1,3-thiazine (Compound I-9)

To a mixture of 2-(2-methoxybenzyl)imino-5,5-dimethyl-1,3-thiazine(0.27 g), carbon disulfide (0.09 g) and N,N-dimethylformamide (2 ml) was added under ice-cooling 60% sodium hydride (0.05 g). The mixture was stirred for 30 minutes. Methyl iodide (0.17 g) was added thereto. The mixture was stirred at room temperature for 2 hours. To the solution was added water (30 ml). The mixture was extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2-(2-methoxybenzyl)imino-3-(methylthio)thiocarbonyl-5,5-dimethyl-1,3-thiazine (0.20 g, yield: 57%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃) 1.25 (6H, s), 2.56 (3H, s), 2.72 (2H, s), 3.85 (3H, s), 4.43 (2H, s), 4.63 (2H, s), 6.86-6.88(2H, m), 7.20-7.30 (1H, m), 7.44-7.48 (1H, m).

Reference Example 9 Preparation of (2-methoxyphenethyl)isothiocyanate (Compound 12)

To a solution of 2-methoxyphenethylamine (1.98 g) in diethylether (20 ml) was added dropwise under ice-cooling thiophosgene (1.54 g). The mixture was stirred at room temperature for 1 hour. To the solution was added water (30 ml). The mixture was extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (2-methoxyphenethyl)isothiocyanate (1.80 g, yield: 71%) as brown oil.

¹H-NMR (δ ppm TMS/CDCl₃) 3.00(2H, t, J=7.4), 3.70(2H, t, J=7.4), 3.86(3H, s), 6.88-6.95(2H, m), 7.15(1H, d, J=7.4), 7.24(1H, t, J=7.4).

Reference Example 10 Preparation of N-(2-methoxyphenethyl)-N′-(1-hydroxy-2,2-dimethyl)propylthiourea (Compound 13)

To a solution of (2-methoxyphenethyl)isothiocyanate (2.35 g) in diethylether (20 ml) was added 3-amino-2,2-dimethylpropanol (1.34 g). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give N-(2-methoxyphenethyl)-N′-(1-hydroxy-2,2-dimethyl)propylthiourea (2.45 g, yield 89%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃) 0.82(6H, s), 2.90(2H, t, J=7.4), 3.25(2H, s), 3.55(2H, d, J=6.3), 3.70(2H, t, J=7.4), 3.86(3H, s), 6.50(1H, brs), 6.88-6.95(2H, m), 7.15(1H, m), 7.24(1H, m).

Reference Example 11 Preparation of 2-(2-methoxyphenethyl)imino-5,5-dimethyl-1,3-thiazine (Compound 14)

To a mixture of N-(2-methoxyphenethyl)-N′-(1-hydroxy-2,2-dimethyl)propylthiourea (2.40 g), triphenylphosphine (2.12 g) and tetrahydrofuran (20 ml) was added dropwise for 10 minutes diethyl azodicarboxylate (2.28 g). The mixture was stirred at room temperature for 2 hours. To the solution was added water (40 ml). The mixture was extracted with dichloromethane (90 ml), dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2-(2-methoxyphenethyl)imino-5,5-dimethyl-1,3-thiazine (0.70 g, yield: 31%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃) 1.05(6H, s,), 2.72(2H, s), 2.80(2H, t, J=7.4), 3.25(2H, s), 3.55(2H, d, J=6.3), 3.83(3H, s), 6.83-6.95(2H, m), 7.15(1H, m), 7.24(1H, m).

The following Examples 10 and 11 were carried out by using 2-(2-methoxyphenethyl)imino-5,5-dimethyl-1,3-thiazine prepared in Example 11.

Example 10 Preparation of 3-(ethylthiocarbonyl)-2-(2-methoxyphenethyl)imino-5,5-dimethyl-1,3-thiazine (Compound I-10)

To a mixture of 2-(2-methoxyphenethyl)imino-5,5-dimethyl-1,3-thiazine (0.28 g), triethylamine (0.15 g) and dichloromethane (5 ml) was added dropwise for 3 minutes ethyl chlorothiocarbonate (0.15 g). The mixture was stirred at room temperature for 2 hours. To the solution was added water (30 ml). The mixture was extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2-(2-methoxyphenethyl)imino-N-(ethylthiocarbamoyl)-5,5-dimethyl-1,3-thiazine (0.21 g, yield: 60%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃) 1.11 (6H, s), 1.26 (3H, t, J=7.4), 2.61 (2H, s), 2.83 (2H, q, J=7.4), 2.99-3.05 (2H, m), 3.61-3.66 (2H, m), 3.62 (2H, s), 3.82 (3H, s), 6.86-6.91 2H, m), 7.17-7.26 (2H, m).

Example 11 Preparation of 2-(2-methoxyphenethyl)imino-3-(methylthio)thiocarbonyl-5,5-dimethyl-1,3-thiazine (Compound I-11)

To a mixture of 1-(1-methoxyphenethyl)imino-5,5-dimethyl-1,3-thiazine (0.28 g), carbondisulfide (0.09 g) and N,N-dimethylformamide (2 ml) was added under ice-cooling 60% sodium hydride (0.05 g). The mixture was stirred for 30 minutes. Methyliodide (0.17 g) was added thereto. The mixture was stirred at room temperature for 2 hours. To the solution was added water (30 ml). The mixture was extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was chromatographed (n-hexane/ethyl acetate) to give 2-(2-methoxyphenethyl)imino-3-(methylthio)thiocarbonyl-5,5-dimethyl-1,3-thiazine (0.18 g, yield: 50%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃) 1.19 (6H, s), 2.55 (3H,s), 2.64 (2H, s), 3.05 (2H, t, J=7.5), 3.66 (2H, t, J=7.5), 3.84 (3H, s), 4.35 (2H, s), 6.84-6.91 (2H, m), 7.17-7.30 (2H, m).

The compounds shown in the following tables were prepared in accordance with the above Example. The numbers of left column in Tables represent Compound No. TABLE 1

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ I-16 H H H H H COSEt Me Me I-17 F H H H H COSEt Me Me I-18 Cl H H H H COSEt Me Me I-19 Me H H H H COSEt Me Me I-20 Et H H H H COSEt Me Me I-21 Pr H H H H COSEt Me Me I-22 Bu H H H H COSEt Me Me I-23 Bu^(s) H H H H COSEt Me Me I-24 Bu^(t) H H H H COSEt Me Me I-25 Ph H H H H COSEt Me Me I-26 CF3 H H H H COSEt Me Me I-27 OMe H H H H COSEt Me Me I-28 QEt H H H H COSEt Me Me I-29 OPr^(i) H H H H COSEt Me Me I-30 SMe H H H H COSEt Me Me I-31 SEt H H H H COSEt Me Me I-32 SPr^(i) H H H H COSEt Me Me I-33 NMe₂ H H H H COSEt Me Me I-34 H Pr^(i) H H H COSEt Me Me I-35 H H Cl H H COSEt Me Me I-36 H H Pr^(i) H H COSEt Me Me I-37 H H NO₂ H H COSEt Me Me I-38 Me Me H H H COSEt Me Me I-39 Me H Me H H COSEt Me Me I-40 Me H H Me H COSEt Me Me I-41 Me H H H Me COSEt Me Me I-42 H Me Me H H COSEt Me Me I-43 H Me H Me H COSEt Me Me I-44 Me H Cl H H COSEt Me Me

TABLE 2

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ I-45 Cl H Me H H COSEt Me Me I-46 Pr^(i) H NO₂ H H COSEt Me Me I-47 Pr^(i) H H H NO₂ COSEt Me Me I-48 NO2 H NO₂ H H COSEt Me Me I-49 Pr H H H H COSMe Me Me I-50 Pr^(i) H H H H COSMe Me Me I-51 Bu^(s) H H H H COSMe Me Me I-52 H Pr^(i) H H H COSMe Me Me I-53 H OMe OMe H H COSMe Me Me I-54 H —OCH₂O— H H COSMe Me Me I-55 H OMe OMe OMe H COSMe Me Me I-56 Et H H H H CSSMe Me Me I-57 Bu^(s) H H H H CSSMe Me Me I-58 CH₂OMe H H H H CSSMe Me Me I-59 CH(Me)OMe H H H H CSSMe Me Me I-60 OMe H H H H CSSMe Me Me I-61 OEt H H H H CSSMe Me Me I-62 SMe H H H H CSSMe Me Me I-63 SEt H H H H CSSMe Me Me I-64 SPr^(i) H H H H CSSMe Me Me I-65 SOMe H H H H CSSMe Me Me I-66 SO₂Me H H H H CSSMe Me Me I-67 SOEt H H H H CSSMe Me Me I-68 NMe₂ H H H H CSSMe Me Me I-69 H Pr^(i) H H H CSSMe Me Me I-70 H H Cl H H CSSMe Me Me

TABLE 3

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ I-71 Me H Me H H CSSMe Me Me I-72 Me H H Me H CSSMe Me Me I-73 Me H H H Me CSSMe Me Me I-74 H Me Me H H CSSMe Me Me I-75 H Me H Me H CSSMe Me Me I-76 OMe OMe H H H CSSMe Me Me I-77 H OMe OMe H H CSSMe Me Me I-78 OMe H H OMe H CSSMe Me Me I-79 OMe H OMe H CSSMe Me Me I-80 H —OCH₂O— H H CSSMe Me Me I-81 Pr^(i) H NO₂ H H CSSMe Me Me I-82 Pr^(i) H H H NO₂ CSSMe Me Me I-83 H OMe OMe OMe H CSSMe Me Me I-84 Pr^(i) H H H H CSSEt Me Me I-85 Bu^(i) H H H H CSSEt Me Me I-86 OEt H H H H CSSEt Me Me I-87 SMe H H H H CSSEt Me Me I-88 H Pr^(i) H H H CSSEt Me Me  I-118 H OEt OEt H H CSSMe Me Me  I-119 OMe H Me H H CSSMe Me Me  I-120 OMe H H Me H CSSMe Me Me  I-121 H OMe Me H H CSSMe Me Me  I-122 Me Me H H H CSSMe Me Me  I-123 N(Me)Ac H H H H CSSMe Me Me

TABLE 4

R⁶ R⁷ R⁸ I-89 COPr Me Me I-90 COOMe Me Me I-91 COOPr Me Me I-92 CONHEt Me Me I-93 COCH₂OMe Me Me I-94 COCH₂SMe Me Me I-95 COCH₂SEt Me Me I-96 CSOEt Me Me I-97 CSNHEt Me Me I-98 CSSPr Me Me I-99 CSSPr^(i) Me Me  I-100 CSSBn Me Me

TABLE 5

R¹ R² R³ n R⁶ R⁷ R⁸ I-101 H H Cl 1 COSEt Me Me I-102 H H CI 1 CSSMe Me Me I-103 Cl H Cl 2 COSEt Me Me I-104 Cl H Cl 2 CSSMe Me Me

TABLE 6

R⁶ W I-105 COSEt

I-106 COSEt

I-107 COSEt

I-108 COSEt

I-109 COSEt

I-110 COSEt

I-111 COSEt

I-112 COSEt

I-113 CSSMe

I-114 CSSMe

I-115 CSSMe

I-116 CSSMe

I-117 CSSMe

TABLE 7

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ I-124 H H OEt H H CSSMe Me Me I-125 H OEt H H H CSSMe Me Me I-126 H H OMe H H CSSMe Me Me I-127 H OMe H H H CSSMe Me Me I-128 H QEt OMe H H CSSMe Me Me I-129 H OPr OMe H H CSSMe Me Me I-130 H OEt OEt H H CSSMe Me Me I-131 H H OPr H H CSSMe Me Me I-132 H OPr H H H CSSMe Me Me I-133 H H OBu H H CSSMe Me Me I-134 H OBu H H H CSSMe Me Me I-135 H OMe OEt H H CSSMe Me Me I-136 H OMe OPr H H CSSMe Me Me I-137 H OBu OMe H H CSSMe Me Me I-138 H H OPr^(i) H H CSSMe Me Me I-139 H OPr^(i) H H H CSSMe Me Me I-140 H H H H H CSSMe Me Me I-141 F H H H H CSSMe Me Me I-142 Cl H H H H CSSMe Me Me I-143 H CI H H H CSSMe Me Me I-144 Me H H H H CSSMe Me Me I-145 H Me H H H CSSMe Me Me I-146 H H Me H H CSSMe Me Me I-147 H Bu H H H CSSMe Me Me I-148 H H Bu H H CSSMe Me Me

TABLE 8

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ I-149 Bu^(t) H H H H CSSMe Me Me I-150 H H Et H H CSSMe Me Me I-151 H Et H H H CSSMe Me Me I-152 H H F H H CSSMe Me Me I-153 H F H H H CSSMe Me Me I-154 H H Pr^(i) H H CSSMe Me Me I-155 H H Morpho- H H CSSMe Me Me lino I-156 H Ac H H H CSSMe Me Me I-157 H H Br H H CSSMe Me Me I-158 H Br H H H CSSMe Me Me I-159 Br H H H H CSSMe Me Me I-160 H C(Me)═ H H H CSSMe Me Me NOMe I-161 H H Ac H H CSSMe Me Me I-162 H H C(Me)═ H H CSSMe Me Me NOMe I-163 OPr^(i) H H H H CSSMe Me Me I-164 Pr H H H H CSSMe Me Me I-165 CF₃ H H H H CSSMe Me Me I-166 H H OPh H H CSSMe Me Me I-167 H H Pr H H CSSMe Me Me I-168 H H Bu^(t) H H CSSMe Me Me I-169 H CF₃ H H H CSSMe Me Me I-170 H H CF₃ H H CSSMe Me Me I-171 Pr^(i) H NHAc H H CSSMe Me Me I-172 Pr^(i) H H H NHAc CSSMe Me Me I-173 H COOMe H H OMe CSSMe Me Me

TABLE 9

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ I-174 Morpho- H H H H CSSMe Me Me lino I-175 H Mor- H H H CSSMe Me Me pholino I-176 Pr^(i) H H COOEt H CSSMe Me Me I-177 H H Piperi- H H CSSMe Me Me dino I-178 Pyrroli- H H H H CSSMe Me Me dino I-179 H SMe H H H CSSMe Me Me I-180 H H SMe H H CSSMe Me Me I-181 OCF₃ H H H H CSSMe Me Me I-182 H OCF₃ H H H CSSMe Me Me I-183 H H OCF₃ H H CSSMe Me Me I-184 H H 3- H H CSSMe Me Me Pyridyl I-185 H 3- H H H CSSMe Me Me Pyridyl I-186 3-Pyridyl H H H H CSSMe Me Me I-187 OPh H H H H CSSMe Me Me I-188 H OEt OEt H H COOMe Me Me I-189 OMe H H H H COOMe Me Me I-190 H H Et H H COOMe Me Me I-191 H H Pr^(i) H H COOMe Me Me I-192 OMe H H H H COSMe Me Me I-193 H H Et H H COSMe Me Me I-194 H H Pr^(i) H H COSMe Me Me I-195 H H OEt H H COSMe Me Me I-196 H OMe OEt H H COSMe Me Me I-197 H Piperi- H H H CSSMe Me Me dino I-198 H H NEt₂ H H CSSMe Me Me

TABLE 10

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ I-199 OMe H COOMe H H CSSMe Me Me I-200 H 2- H H H CSSMe Me Me Oxopyrro- lidino I-201 H OPh H H H CSSMe Me Me I-202 H H Ph H H CSSMe Me Me I-203 Ph H H H H CSSMe Me Me I-204 H Ph H H H CSSMe Me Me I-205 Pr^(i) H H H H CSOMe Me Me I-206 Pr^(i) H I H H CSSMe Me Me I-207 OMe H (Morpho- H H CSSMe Me Me lino)CO I-208 H H NMe₂ H H CSSMe Me Me I-209 H NMe₂ H H H CSSMe Me Me I-210 N(Me)Et H H H H CSSMe Me Me I-211 N(Me)Pr H H H H CSSMe Me Me I-212 NEt₂ H H H H CSSMe Me Me I-213 F H H H F CSSMe Me Me I-214 Pr^(i) H Cl H H CSSMe Me Me I-215 NMe₂ Me H H H CSSMe Me Me I-216 NMe₂ H Me H H CSSMe Me Me I-217 NMe₂ H H Me H CSSMe Me Me I-218 NMe₂ H H Cl H CSSMe Me Me I-219 Me H H H Me CSSMe Me Me I-220 NMe₂ H H H H CSSEt Me Me I-221 H NMe₂ H H H CSSEt Me Me I-222 NMe₂ H Me H H OSSEt Me Me I-223 H H Pr^(i) H H OSSEt Me Me

TABLE 11

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ I-224 OMe H CONHMe H H CSSMe Me Me I-225 OCHF₂ H H H H CSSMe Me Me I-226 H OCHF₂ H H H CSSMe Me Me I-227 H NEt₂ H H H CSSMe Me Me I-228 NMe₂ H Cl H H CSSMe Me Me I-229 NMe₂ H F H H CSSMe Me Me I-230 NMe₂ H H F H CSSMe Me Me I-231 NMe₂ H Et H H CSSMe Me Me I-232 NMe₂ H H Et H CSSMe Me Me I-233 NMe₂ H CI H H CSSEt Me Me I-234 NMe₂ H F H H CSSEt Me Me I-235 NMe₂ H Et H H CSSEt Me Me I-236 Pr^(i) H H H H CSSBu^(s) Me Me I-237 Pr^(i) H H H H CSSBu^(i) Me Me I-238 Pr^(i) H H H H CSNHMe Me Me I-239 Me NMe₂ H H H CSSMe Me Me I-240 NMe² OMe H H H CSSMe Me Me I-241 H NMe₂ Me H H CSSMe Me Me I-242 NMe² Cl H H H CSSMe Me Me I-243 H NMe₂ OMe H H CSSMe Me Me I-244 Pr^(i) H H H H CSSEt Et Et I-245 Pr^(i) H H H H Me Me Me I-246 Pr^(i) H H H H Pr Me Me I-247 Pr^(i) H H H H Pr^(i) Me Me I-248 Pr^(i) H H H H Bu^(i) Me Me

TABLE 12

A R⁶ R⁷ R⁸ I-249

CSSMe Me Me I-250

CSSMe Me Me I-251

CSSMe Me Me I-252

CSSMe Me Me I-253

CSSMe Me Me I-254

CSSMe Me Me I-255

CSSMe Me Me I-256

CSSMe Me Me I-257

CSSMe Me Me I-258

CSSMe Me Me I-259

CSSMe Me Me I-260

CSSMe Me Me I-261

CSSMe Me Me

TABLE 13

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ I-262 NMe₂ H OMe H H CSSMe Me Me I-263 NMe₂ H H OMe H CSSMe Me Me I-264 Me NEt₂ H H H CSSMe Me Me I-265 H NEt₂ Me H H CSSMe Me Me I-266 H NEt₂ OMe H H CSSMe Me Me I-267 Bu^(s) H H H H CSSMe Et Et I-268 Pr^(i) H H H H CSSMe Pr Pr I-269 Pr^(i) H H H H CSSMe —(CH₂)₄— I-270 Pr^(i) H H H H CSSMe —(CH₂)₅—

TABLE 14

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ I-271 Pr^(i) H H H H SO₂Me Me Me I-272 Pr^(i) H H H H

Me Me I-273 Pr^(i) H H H H

Me Me I-274 H Pr^(i) H H H

Me Me I-275 H Pr^(i) H H H SO₂Et Me Me I-276 H Pr^(i) H H H

Me Me I-277 H Pr^(i) H H H

Me Me I-278 H Pr^(i) H H H

Me Me I-279 H Pr^(i) H H H

Me Me I-280 H Pr^(i) H H H

Me Me Physical Date (M.p., ¹H-NMR) of the compounds in the above Tables are shown in the following Tables.

TABLE 15 Comp. No. Physical Date No M.p. I-16 57-59° C. 1.16(6H, s), 1.31(3H, t, J=7.3), 2.64(2H, s), 2.91(2H, q, J=7.3), 3.78(2H, s), 6.96(1H, dd, J=7.4, 1.2), 7.14(1H, t, J=7.4), 7.36(2H, t, J=7.4). I-17 1.15(6H, s), 1.31(3H, t, J=7.3), 2.67(2H, s), 2.91(2H, q J=7.3), 3.77(2H, s), 7.10-7.15(4H, m). I-18 1.16(6H, s), 1.31(3H, t, J=7.3), 2.68(2H, s), 2.92(2H,(q, J=7.3), 3.80(2H, s), 6.96(1H, dd, J=7.7, 1.2), 7.08(1H, dt, J=7.7, 1.6), 7.25(2H, t, J=7.4), 7.40(1H, d, J=7.4). I-19 1.15(6H, s), 1.27(3H, t, J=7.3), 2.24(3H, s), 2.62(2H, s), 2.92(2H, q, J=7.4), 3.77(2H, s), 6.83(1H, d, J=7.7), 7.04(1H, t, J=7.7), 7.16-7.22(2H, m). I-20 1.15(6H, s), 1.19(3H, t, J=7.4), 1.31(3H, t, J=7.3), 2.62(2H, q, J=7.3), 2.65(2H, s), 2.94(2H, q, J=7.4), 3.77(2H, s), 6.83(1H, d, J=7.6), 7.10-7.22(3H, m). I-21 0.95(3H, t, J=7.3), 1.15(6H, s), 1.30(3H, t, J=7.4), 1.50-1.64(2H, m), 2.56(2H, q, J=7.3), 2.59(2H, s), 2.90(2H, q, J=7.4), 3.76(2H, s), 6.82(1H, d, J=7.3), 7.06-7.28(3H, m). I-22 0.90(3H, t, J=7.1), 1.15(6H, s), 1.29(3H, t, J=7.4), 1.30-1.34(2H, m), 1.52-1.58(2H, m), 2.54(2H, q, J=7.1), 2.62(2H, s), 2.92(2H, q, J=7.4), 3.76(2H, s), 6.79(1H, dd, J=7.9, 1.4), 7.06-7.28(3H, m). I-23 0.86(3H, t, J=7.4), 1.14(6H, s), 1.16(6H, d, J=6.9), 1.29(3H, t, J=7.4), 1.48-1.58(2H, m), 2.61(2H, s), 2.89(2H, q, J=7.4), 2.88-2.92(1H, m), 3.76(2H, d, J=13.6), 3.82(1H, d, J=13.6), 6.82-6.88(1H, m), 7.10-7.18(1H, m), 7.23-7.29(1H, m). I-24 1.15(6H, s), 1.27(3H, t, J=7.4), 1.33(9H, s), 2.68(2H, s), 2.86(2H, q, J=7.4), 3.75(2H, s), 6.86(1H, dd, J=7.4, 1.6), 7.08-7.19(2H, m), 7.38(2H, dd, J=7.4, 1.6). I-25 0.99(6H, s), 1.25(3H, t, J=7.4), 2.45(2H, s), 2.82(2H, q, J=7.4), 3.51(2H, s), 6.98(1H, d, J=7.7), 7.20-7.36(6H, m), 7.43(2H, m). I-26 82-83° C. 1.15(6H, s), 1.29(3H, t, J=7.3), 2.66(2H, s), 2.89(2H, q, J=7.4), 3.77(2H, s), 6.98(1H, d, J=7.6), 7.19(1H, t, J=7.6), 7.49(1H, t, J=7.6), 7.64(1H, d, J=7.6).

TABLE 16 Comp. No. Physical Date No M.p. I-27 1.16(6H, s), 1.25(3H, t, J=7.4), 2.62(2H, s), 2.88(2H, q, J=7.4), 3.78(2H, s), 3.83(3H, s), 6.91-6.96(3H, m), 7.05-7.14(1H, m). I-28 1.15(6H, s), 1.30(3H, t, J=7.4), 1.40(3H, t, J=7.0), 2.60(2H, s), 2.90(2H, q, J=7.4), 3.78(2H, s), 4.08(2H, q, J=7.0), 6.90-6.94(3H, m), 7.06-7.08(1H, m). I-29 1.14(6H, s), 1.29(6H, d, J=7.4), 1.31(6H, d, J=6.0), 2.59(2H, s), 2.89(2H, q, J=7.4), 3.76(2H, s), 4.50(1H, q, J=6.0), 6.90-6.93(3H, m), 7.01-7.07(1H, m). I-30 78-80° C. 1.15(6H, s), 1.29(3H, t, J=7.4), 2.43(3H, s), 2.63(2H, s), 2.89(2H, q, J=7.4), 3.78(2H, s), 6.87-6.91(1H, m), 7.05-7.14(2H, m), 7.20-7.29(1H, m). I-31 55-57° C. 1.15(6H, s), 1.29(3H, t, J=7.4), 1.31(3H, t, J=7.4), 2.66(2H, s), 2.89(2H, q, J=7.4), 2.94(2H, q, J=7.4), 3.78(2H, s), 6.91(1H, dd, J=7.4, 1.6), 7.08-7.20(2H, m), 7.32(1H, dd, J=7.4, 1.6). I-32 1.15(6H, s), 1.27(6H, d, J=6.6), 1.28(6H, d, J=7.4), 2.65(2H, s), 2.88(2H, q, J=7.4), 3.38-3.42(1H, m), 3.78(2H, s), 6.90(1H, dd, J=7.7, 1.6), 7.08-7.20(2H, m), 7.32(1H, dd, J=7.7, 1.6). I-33 1.15(6H, s), 1.29(3H, t, J=7.4), 2.60(2H, s), 2.71(6H, s), 2.89(2H, q, J=7.4), 3.77(2H, s), 6.90-6.98(3H, m), 7.05-7.10(1H, m). I-34 1.16(6H, s), 1.27(6H, d, J=6.9), 1.31(3H, t, J=7.4), 2.64(2H, s), 2.91(2H, q, J=7.4), 2.98(1H, q, J=6.9), 3.77(2H, s), 6.78-6.83(2H, m), 7.01-7.04(1H, m), 7.25-7.27(1H, m). I-35 68-69° C. 1.16(6H, s), 1.30(3H, t, J=7.3), 2.66(2H, s), 2.90(2H, q, J=7.3), 3.76(2H, s) 6.98(2H, dd, J=6.6, 2.1), 7.31(2H, dd, J=6.6, 2.1). I-36 67-69° C. 1.15(6H, s), 1.20(6H, d, J=6.9), 1.26(3H, t, J=7.4), 2.64(2H, s), 2.86(2H, q, J=7.4), 2.89(1H, q, J=6.9), 3.75(2H, s), 6.98(2H, d, J=8.2), 7.20(2H, d, J=8.3). I-37 125-126° C.  1.15(6H, s), 1.30(3H, t, J=7.3), 2.72(2H, s), 2.92(2H, q, J=7.3), 3.78(2H, s), 7.05(2H, d, J=8.3), 7.31(2H, d, J=8.3). I-38 76-78° C. 1.15(6H, s), 1.30(3H, t, J=7.4), 2.14(3H, s), 2.29(3H, s), 2.63(2H, s), 2.89(2H, q, J=7.4), 3.77(2H, s), 6.70(1H, d, J=7.9), 6.94(1H, d, J=7.9), 7.06(1H, s).

TABLE 17 Comp. No. Physical Date No M.p. I-39 1.14(6H, s), 1.29(3H, t, J=7.4), 2.21(3H, s), 2.32(3H, s), 2.65(2H, s), 2.89(2H, q, J=7.4), 3.76(2H, s), 6.73(1H, d, J=7.9), 6.97(1H, d, J=7.9), 7.02(1H, s). I-40 1.15(6H, s), 1.30(3H, t, J=7.4), 2.19(3H, s), 2.31(3H, s), 2.64(2H, s), 2.89(2H, q, J=7.4), 3.77(2H, s), 6.65(1H, s), 6.86(1H, d, J=7.9), 7.07(1H, d, J=7.7). I-41 59-61° C. 1.15(6H, s), 1.30(3H, t, J=7.3), 2.19(6H, s), 2.62(2H, s), 2.90(2H, q, J=7.3), 3.78(2H, s), 6.90-6.96(1H, m), 7.02-7.08(2H, m). I-42 1.15(6H, s), 1.31(3H, t, J=7.4), 2.26(3H, s), 2.28(3H, s), 2.65(2H, s), 2.91(2H, q, J=7.4), 3.78(2H, s), 6.74(1H, dd, J=7.9, 1.8), 6.80(1H, d, J=1.8), 7.13(1H, d, J=7.7). I-43 1.15(6H, s), 1.31(3H, t, J=7.4), 2.31(6H, s), 2.63(2H, s), 2.90(2H, q, J=7.4), 3.76(2H, s), 6.58(2H, s), 6.77(1H, s). I-44 1.15(6H, s), 1.28(3H, t, J=7.4), 2.21(3H, s), 2.64(2H, s), 2.90(2H, q, J=7.4), 3.76(2H, s), 6.74(1H, d, J=8.2), 7.10-7.18(2H, m). I-45 1.15(6H, s), 1.28(3H, t, J=7.4), 2.31(3H, s), 2.66(2H, s), 2.92(2H, q, J=7.4), 3.78(2H, s), 6.74(1H, d, J=7.8), 7.04(1H, d, J=7.8), 7.25(1H, d, J=7.8). I-46 119-120° C.  1.16(6H, s), 1.25(6H, d, J=6.9), 1.29(3H, t, J=7.4), 2.69(2H, s), 2.90(2H, q, J=7.4), 3.15(1H, m), 3.79(2H, s), 6.92(1H, d, J=8.7), 8.01(1H, dd, J=8.5, 2.4), 8.18(1H, d, J=2.4). I-47 1.17(6H, s), 1.23(6H, d, J=6.9), 1.30(3H, t, J=7.4), 2.69(2H, s), 2.91(2H, q, J=7.4), 3.19(1H, m), 3.79(2H, s), 7.41(1H, d, J=8.7), 7.71(1H, d, J=2.4), 7.92(1H, dd, J=8.7, 2.4). I-48 1.15(6H, s), 1.30(3H, t, J=7.4), 2.73(2H, s), 2.93(2H, q, J=7.4), 3.82(2H, s) 7.15(2H, d, J=8.3), 8.48(1H, dd, J=8.3, 1.4), 8.90(1H, d, J=8.3). I-49 64-66° C. 0.95(3H, t, J=7.3), 1.15(6H, s), 1.50-1.64(2H, m), 2.32(3H, s), 2.56(2H, q, J=7.3), 2.63(2H, s), 3.78(2H, s), 6.82(1H, d, J=7.3), 7.06-7.28(3H, m). I-50 95-96° C. 1.16(6H, s), 1.20(6H, d, J=6.9), 2.32(3H, s), 2.64(2H, s), 3.12(1H, q, J=6.9), 3.79(2H, s), 6.78-6.82(1H, m), 7.11-7.20(2H, m), 7.30-7.34(1H, m).

TABLE 18 Comp No. Physical Date No M.p. I-51  53-56° C. 0.85(3H, t, J=7.3), 1.15(6H, d, J=6.9), 1.18(6H, s), 1.57-1.70(2H, m), 2.31(3H, s), 2.62(2H, s), 2.91(1H, q, J=6.9), 3.74(1H, d, J=13.7), 3.78(1H, d, J=13.7), 6.78-6.83(1H, m), 7.11-7.18(2H, m), 7.23-7.30(1H, m). I-52  88-90° C. 1.17(6H, s), 1.27(6H, d, J=6.9), 2.33(3H, s), 2.65(2H, s), 2.91(1H, q, J=6.9), 3.79(2H, s), 6.78-6.83(2H, m), 7.01-7.04(1H, m), 7.20-7.24(1H, m). I-53 1.16(6H, s), 2.32(3H, s), 2.65(2H, s), 3.77(2H, s), 3.87(6H, s), 6.51-6.59(2H, m), 6.80-6.89(1H, m). I-54 102-104° C. 1.15(6H, s), 2.31(3H, s), 2.65(2H, s), 3.76(2H, s), 5.96(2H, s), 6.42(1H, dd, J=8.1, 1.8), 6.53(1H, d, J=1.8), 6.78(1H, d, J=8.1). I-55 129-131° C. 1.16(6H, s), 2.32(3H, s), 2.67(2H, s), 3.78(2H, s), 3.85(6H, s), 3.86(3H, s), 6.20(2H, s) I-56 107-109° C. 1.17(3H, t, J=7.6), 1.22(6H, s), 2.58(2H, q, J=7.6), 2.64(3H, s), 2.66(2H, s), 4.51(2H, s), 6.91(1H, dd, J=7.5, 1.3), 7.02-7.19(2H, m), 7.23-7.28(1H, m). I-57 0.85(3H, t, J=7.3), 1.18(6H, d, J=6.9), 1.23(6H, s), 1.57-1.70(2H, m), 2.64(3H, s), 2.66(2H, s), 2.88(1H, q, J=6.9), 4.38(1H, d, J=13.7), 4.60(1H, d, J=13.7), 6.83-6.90(1H, m), 7.11-7.18(2H, m), 7.28-7.35(1H, m). I-58  85-87° C. 1.22(6H, s), 2.62(3H, s), 2.63(2H, s), 3.35(3H, s), 4.40(2H, s), 4.48(2H, s), 6.93-6.99(1H, m), 7.11-7.29(2H, m), 7.40-7.49(1H, m). I-59 113-114° C. 1.22(3H, s), 1.24(3H, s), 1.37(3H, d, J=6.4), 2.63(3H, s), 2.65(2H, s), 3.24(3H, s), 4.35(1H, d, J=13.6), 4.55(1H, q, J=6.4), 4.66(1H, d, J=13.6), 6.91(1H, d, J=7.4), 7.19-7.40(2H, m), 7.51(1H, d, J=7.4). I-60 128-130° C. 1.22(6H, s), 2.62(3H, s), 2.65(2H, s), 3.85(3H, s), 4.53(2H, s), 6.93-6.99(2H, m), 7.02-7.15(2H, m). I-61 100-101° C. 1.26(6H, s), 1.43(3H, t, J=7.4), 2.66(2H, s), 2.67(3H, s), 4.08(2H, q, J=7.0), 4.55(2H, s), 6.95-6.99(3H, m), 7.11-7.18(1H, m). I-62 137-139° C. 1.23(6H, s), 2.43(3H, s), 2.64(3H, s), 2.67(2H, s), 4.53(2H, s), 6.87-6.92(1H, m), 7.11-7.20(2H, m), 7.23-7.29(1H, m).

TABLE 19 Comp. No. Physical Date No M.p. I-63 103-105° C. 1.15(6H, s), 1.29(3H, t, J=7.4), 1.31(3H, t, J=7.4), 2.66(2H, s), 2.89(2H, q, J=7.4), 2.94(2H, q, J=7.4), 3.78(2H, s), 6.91(1H, dd, J=7.4, 1.6), 7.08-7.20(2H, m), 7.32(1H, dd, J=7.4, 1.6). I-64 125-126° C. 1.24(6H, s), 1.28(6H, d, J=6.6), 2.63(3H, s), 2.66(2H, s), 3.38-3.42(1H, m), 4.53(2H, s), 6.97(1H, dd, J=7.7, 1.6), 7.08-7.20(2H, m), 7.32(1H, dd, J=7.7, 1.6). I-65 1.22(6H, s), 2.63(3H, s), 2.65(2H, d, J=13.6), 2.75(3H, s), 4.17(1H, d, J=13.6), 4.77(1H, d, J=13.6), 7.06(1H, dd, J=7.7, 1.7), 7.19-7.40(2H, m), 7.97(1H, dd, J=7.7, 1.7). I-66 147-149° C. 1.23(6H, s), 2.63(3H, s), 2.71(2H, s), 3.13(3H, s), 4.52(2H, s), 7.11(1H, m,), 7.11-7.20(2H, m), 7.23-7.29(1H, m). I-67 129-130° C. 1.22(6H, s), 1.23(3H, t, J=6.9), 2.63(3H, s), 2.66(2H, s), 2.70-2.85(1H, m), 2.90-3.15(1H, m), 4.25(1H, d, J=13.6), 4.70(1H, d, J=13.6), 7.06(1H, d, J=7.5), 7.30-7.45(2H, m), 7.90(1H, d, J=7.5). I-68 100-102° C. 1.23(6H, s), 2.62(3H, s), 2.65(2H, s), 2.71(6H, s), 4.50(2H, s), 6.93-6.99(3H, m), 7.02-7.15(1H, m). I-69 1.23(6H, s), 1.25(6H, d, J=6.9), 2.64(3H, s), 2.66(2H, s), 2.92(1H, q, J=6.9), 4.52(2H, s), 6.84-6.86(2H, m), 7.08-7.13(1H, m), 7.28-7.32(1H, m). I-70 116-118° C. 1.23(6H, s), 2.64(3H, s), 2.68(2H, s), 4.51(2H, s), 6.97(2H, d, J=8.6), 7.35(2H, d, J=8.6). I-71 103-105° C. 1.22(6H, s), 2.19(3H, s), 2.30(3H, s), 2.63(3H, s), 2.65(2H, s), 4.50(2H, s), 6.79(1H, d, J=7.9), 6.98(1H, d, J=7.9), 7.02(1H, s). I-72 100-101° C. 1.23(6H, s), 2.18(3H, s), 2.32(3H, s), 2.64(3H, s), 2.65(2H, s), 4.51(2H, s), 6.71(1H, s), 6.88(1H, d, J=7.9), 7.08(1H, t, J=7.9). I-73  93-95° C. 1.22(6H, s), 2.12(3H, s), 2.30(3H, s), 2.64(3H, s), 2.65(2H, s), 4.51(2H, s), 6.76(1H, d, J=7.9), 6.98(1H, d, J=7.9), 7.08(1H, t, J=7.9). I-74 126-128° C. 1.23(6H, s), 2.25(3H, s), 2.27(3H, s), 2.64(3H, s), 2.65(2H, s), 4.51(2H, s), 6.76(1H, d, J=7.9), 6.82(1H, s), 713(1H, d, J=7.9). I-75  96-98° C. 1.23(6H, s), 2.32(6H, s), 2.63(3H, s), 2.65(2H, s), 4.51(2H, s), 6.64(2H, s), 6.80(1H, s). I-76 1.22(6H, s), 2.64(3H, s), 2.65(2H, s), 3.79(3H, s), 3.88(3H, s), 4.52(2H, s), 6.60(1H, 4, J=7.9), 6.73(1H, d, J=7.9), 7.04(1H, d, J=7.9).

TABLE 20 Comp. No. Physical Date No M.p. I-77 1.24(6H, s), 2.63(3H, s), 2.68(2H, s), 3.87(6H, s), 4.50(2H, s), 6.61-6.65(2H, m), 6.85-6.89(1H, m). I-78 1.22(6H, s), 2.62(3H, s), 2.66(2H, s), 3.81(6H, s), 4.52(2H, s), 6.48(1H, dd, J=8.5, 2.4), 6.51(1H, d, J=2.4), 6.92(1H, d, J=8.5). I-79 1.22(6H, s), 2.62(3H, s), 2.64(2H, s), 3.77(6H, s), 4.52(2H, s), 6.56(1H, d, J=2.4), 6.68(1H, dd, J=8.5, 2.4), 686(1H, d, J=8.5). I-80 108-110° C. 1.23(6H, s), 2.63(3H, s), 2.66(2H, s), 4.49(2H, s), 6.04(2H, s), 6.50(1H, dd, J=8.1, 1.8), 6.61(1H, d, J=1.8), 6.83(1H, d, J=8.1). I-81 1.23(6H, s), 1.25(6H, d, J=6.9), 2.65(3H, s), 2.71(2H, s), 3.11(1H, q, J=6.9), 4.51(2H, s), 7.02(1H, d, J=8.5), 8.04(1H, dd, J=8.5, 2.7), 8.21(1H, d, J=2.7). I-82 1.21(6H, s), 1.24(6H, d, J=6.9), 2.63(3H, s), 2.66(2H, s), 3.17(1H, q, J=6.9), 4.51(2H, s), 7.45(1H, d, J=8.5), 7.80(1H, d, J=2.4), 7.99(1H, dd, J=8.5, 2.4). I-83 1.24(6H, s), 2.64(3H, s), 2.68(2H, s), 3.85(6H, s), 3.86(3H, s), 4.51(2H, s), 6.28(2H, s). I-84  68-70° C. 1.22(6H, d, J=6.9), 1.23(6H, s), 1.35(3H, t, J=7.4), 2.65(2H, s), 3.11(1H, q, J=6.9), 3.25(2H, q, J=6.9), 4.48(2H, s), 6.89-6.92(1H, m), 7.14-7.20(2H, m), 7.30-7.34(1H, m). I-85 0.85(3H, t, J=7.4), 1.18(6H, d, J=6.9), 1.23(6H, s), 1.35(3H, t, J=7.4), 1.57-1.70(2H, m), 2.56(2H, s), 2.87(1H, q, J=6.9), 3.25(2H, q, J=7.4), 4.35(1H, d, J=13.7), 4.60(1H, d, J=13.7), 6.89-6.92(1H, m), 7.10-7.18(2H, m), 7.30-7.34(1H, m). I-86  96-97° C. 1.23(6H, s), 1.36(3H, t, J=7.0), 1.40(3H, t, J=7.0), 2.63(2H, s), 3.27(2H, q, J=7.4), 4.06(2H, q, J=7.0), 4.51(2H, s), 6.92-7.08(3H, m), 7.11-7.15(1H, m). I-87 105-106° C. 1.22(6H, s), 1.35(3H, t, J=7.4), 2.43(3H, s), 2.66(2H, s), 3.26(2H, q, J=7.4), 4.50(2H, s), 6.95-6.98(1H, m), 7.10-7.17(2H, m), 7.24-7.29(1H, m).

TABLE 21 Comp. No. Physical Date No M.p. I-88 1.23(6H, s), 1.25(6H, d, J=6.9), 1.35(3H, t, J=7.4), 2.66(2H, s), 2.90(1H, q, J=6.9), 3.28(2H, q, J=7.4), 4.50(2H, s), 6.84-6.88(2H, m), 7.08-7.13(1H, m), 7.28-7.32(1H, m). I-89 0.98(3H, t, J=7.4), 1.12(6H, s), 1.22(6H, d, J=6.9), 1.72-1.80(2H, m), 2.58(2H, s), 2.90(2H, t, J=7.4), 3.06(1H, q, J=6.9), 3.71(2H, s), 6.71-6.76(1H, m), 7.11-7.20(2H, m), 7.30-7.34(1H, m). I-90 99-101° C.  1.14(6H, s), 1.21(6H, d, J=6.9), 2.58(2H, s), 3.14(1H, q, J=6.9), 3.64(2H, s), 3.86(3H, s), 6.73-6.78(1H, m), 7.11-7.18(2H, m), 7.28-7.35(1H, m). I-91 1.00(3H, t, J=7.3), 1.14(6H, s), 1.20(6H, d, J=6.9), 1.74(2H, q, J=7.3), 2.58(2H, s), 3.16(1H, q, J=6.9), 3.65(2H, s), 4.23(2H, q, J=6.9), 6.73-6.80(1H, m), 7.12-7.18(2H, m), 7.31-7.34(1H, m). I-92 52-53° C. 1.13(6H, s), 1.19(6H, d, J=6.9), 1.20(3H, t, J=7.4), 2.60(2H, s), 2.98(1H, q, J=6.9), 3.38(2H, q, J=7.4), 3.77(2H, s), 6.73-6.78(1H, m), 7.09-7.18(2H, m), 7.28-7.32(1H, m). I-93 76-78° C. 1.14(6H, s), 1.22(6H, d, J=6.9), 2.62(2H, s), 2.96(1H, q, J=6.9), 3.48(3H, s), 3.75(2H, s), 4.64(2H, s), 6.73-6.78(1H, m), 7.10-7.17(2H, m), 7.25-7.32(1H, m). I-94 61-62° C. 1.14(6H, s), 1.20(6H, d, J=6.9), 2.23(3H, s), 2.68(2H, s), 2.93(1H, q, J=6.9), 3.71(2H, s), 3.94(2H, s), 6.82-6.86(1H, m), 7.10-7.18(2H, m), 7.30-7.36(1H, m). I-95 50-52° C. 1.13(6H, s), 1.20(6H, d, J=6.9), 1.31(3H, t, J=7.3), 2.65(2H, J=7.3), 2.68(2H, s), 2.90(1H, q, J=6.9), 3.71(2H, s), 3.97(2H, s), 6.82-6.86(1H, m), 7.12-7.19(2H, m), 7.30-7.36(1H, m). I-96 73-75° C. 1.21(6H, s), 1.22(6H, d, J=6.9), 1.42(3H, t, J=6.9), 2.61(2H, s), 3.10(1H, q, J=6.9), 4.15(2H, s), 4.65(2H, q, J=6.9), 6.74-6.78(1H, m), 7.14-7.20(2H, m), 7.30-7.34(1H, m). I-97 160-162° C.  1.18(6H, s), 1.22(6H, d, J=6.9), 1.25(3H, t, J=7.4), 2.60(2H, s), 2.90(1H, q, J=6.9), 3.71(2H, q, J=7.4), 4.40(2H, s), 6.74-6.78(1H, m), 7.14-7.20(2H, m), 7.30-7.34(1H, m). I-98 1.04(3H, t, J=7.4), 1.20(6H, d, J=6.9), 1.27(6H, s), 1.73(2H, m), 2.64(2H, s), 3.12(1H, q, J=6.9), 3.22(2H, t, J=7.4), 4.48(2H, s), 6.89-6.92(1H, m), 7.10-7.20(2H, m), 7.28-7.35(1H, m).

TABLE 22 Comp. No. Physical Date No M.p. I-99 113-114° C. 1.04(6H, d, J=6.9), 1.27(6H, s), 1.42(3H, d, J=6.9), 2.63(2H, s), 3.14(1H, q, J=6.9), 4.02(1H, q, J=6.9), 4.46(2H, s), 6.89-6.93(1H, m), 7.10-7.20(2H, m), 7.28-7.35(1H, m). I-100 1.10(6H, d, J=6.9), 1.22(6H, s), 2.64(2H, s), 3.08(1H, q, J=6.9), 4.48(2H, s), 4.49(2H, s), 6.83-6.90(1H, m), 7.11-7.18(2H, m), 7.20-7.38(6H, m). I-101 1.15(6H, s), 1.25(3H, t, J=7.4), 2.70(2H, s), 2.87(2H, q, J=7.4), 3.69(2H, s), 4.55(2H, s), 7.30-7.40(4H, m). I-102 1.24(6H, s), 2.57(3H, s), 2.73(2H, s), 4.43(2H, s), 4.58(2H, s), 7.23-7.40(4H, m). I-103 1.11(6H, s), 1.26(3H, t, J=7.4), 2.61(2H, s), 2.83(2H, q, J=7.4), 3.10(2H, t, J=7.4), 3.65(2H, s), 3.66(2H, t, J=7.4), 7.17(1H, dd, J=8.2, 2.1), 7.30(1H, t, J=8.2), 7.36(1H, d, J=2.1). I-104 1.16(6H, s), 2.55(3H, s), 2.63(2H, s), 3.13(2H, t, J=7.5), 3.69(2H, t, J=7.5), 4.35(2H, s), 7.15(1H, dd, J=8.2, 2.1), 7.25(1H, t, J=8.2), 7.36(1H, d, J=2.1). I-105 1.20(6H, d, J=6.9), 1.30(3H, t, J=7.4), 2.10-2.22(2H, m), 2.88(2H, t, J=6.4), 2.94(2H, q, J=7.4), 3.11(1H, q, J=6.9), 4.05(2H, t, J=7.4), 6.82-6.86(1H, m), 7.10-7.16(2H, m), 7.28-7.34(1H, m). I-106 1.17-1.30(12H, m), 1.45-1.52(1H, m), 1.90-1.96(1H, m), 2.92(2H, q, J=7.4), 2.95-3.05(2H, m), 3.14-3.23(1H, m), 3.72-3.75(1H, m), 7.20-7.30(2H, m), 7.40-7.45(2H, m). I-107 1.22(6H, d, J=6.9), 1.28(3H, d, J=6.6), 1.29(3H, t, J=7.4), 1.75-1.77(1H, m), 2.29-2.34(1H, m), 2.88(2H, q, J=7.4), 3.14(1H, m), 3.31-3.36(1H, m), 4.01-4.10(2H, m), 6.81-6.85(1H, m), 7.10-7.20(2H, m), 7.28-7.35(1H, m). I-108 1.12(3H, d, J=6.6), 1.20(6H, d, J=6.9), 1.29(3H, t, J=7.4), 2.40-2.50(1H, m), 2.57(1H, dd, J=13.5, 6.6), 2.91(2H, q, J=7.4), 2.95(1H, m), 3.14(1H, m), 3.45(1H, dd, J=13.5, 8.4), 4.30(1H, dd, J=13.5, 8.4), 6.81-6.85(1H, m), 7.10-7.20(2H, m), 7.28-7.35(1H, m).

TABLE 23 Comp. No. Physical Date No M.p. I-109 0.88(6H, t, J=7.5), 1.22(6H, d, J=6.9), 1.29(3H, t, J=7.4), 1.45-1.52(4H, m), 2.58(2H, s), 2.89(2H, q, J=7.4), 3.15(1H, m), 3.77(2H, s), 6.78-6.83(1H, m), 7.08-7.21(2H, m), 7.30-7.35(1H, m). I-110 109-111° C. 1.21(6H, d, J=6.9), 1.23(6H, s), 1.25(3H, t, J=7.4), 2.81(2H, q, J=7.4), 2.90(1H, t, J=6.9), 3.05(2H, s), 7.13-7.30(2H, m), 7.36-7.45(2H, m). I-111 1.21(6H, d, J=6.9), 1.31(3H, t, J=7.4), 1.42(3H, d, J=6.7), 2.90(2H, q, J=7.4), 3.23(1H, q, J=6.9), 3.69(1H, q, J=6.6), 3.87-3.93(1H, m), 6.78-6.82(1H, m), 7.08-7.20(2H, m), 7.25-7.30(1H, m). I-112 1.19-1.25(9H, m), 1.14(3H, d, J=6.3), 2.76(1H, d, J=10.9), 2.96(2H, t, J=7.4), 3.22(1H, q, J=6.9), 3.44-3.48(1H, m), 5.12(1H, q, J=6.3), 6.81-6.85(1H, m), 7.09-7.16(2H, m), 7.28-7.32(1H, m). I-113 126-128° C. 1.18(6H, d, J=6.9), 1.22(6H, d, J=6.9), 1.45(3H, t, J=7.4), 1.80-1.91(1H, m), 2.57-2.64(2H, m), 2.61(3H, s), 2.86-2.89(1H, m), 3.07(1H, m), 5.95-6.05(1H, m), 6.98-7.00(1H, m), 7.12-7.22(2H, m), 7.28-7.35(1H, m). I-114 1.20(6H, d, J=6.9), 1.28(3H, d, J=6.9), 1.82-1.88(1H, m), 2.48-2.63(1H, m), 2.63(3H, s), 3.11(1H, m), 3.29-3.35(1H, m), 4.26(1H, m), 4.98(1H, m), 6.90-6.95(1H, m), 7.15-7.20(2H, m), 7.30-7.35(1H, m). I-115 1.14(3H, d, J=6.5), 1.20(6H, d, J=6.9), 2.53(1H, dd, J=13.0, 5.4), 2.75(3H, s), 2.80-2.85(1H, m), 2.95(1H, dd, J=13.0, 5.4), 3.11(1H, m), 3.72(1H, dd, J=13.0, 9.0), 5.15(1H, dd, J=13.0, 9.0), 6.90-6.95(1H, m), 7.15-7.25(2H, m), 7.30-7.35(1H, m). I-116 119-121° C. 0.88(6H, t, J=7.5), 1.20(6H, d, J=6.9), 1.45-1.52(4H, m), 2.62(2H, s), 2.64(3H, s), 3.15(1H, m), 4.66(2H, s), 6.78-6.83(1H, m), 7.08-7.21(2H, m), 7.30-7.35(1H, m). I-117  99-100° C. 0.71-0.79(1H, m), 0.85-0.90(2H, m), 1.22(6H, d, J=6.9), 1.22-1.25(1H, m), 2.61(3H, s), 2.79(3H, s), 3.00-3.05(1H, m), 4.40(2H, s), 6.92-6.95(1H, m), 7.15-7.21(2H, m), 7.30-7.35(1H, m).

TABLE 24 Comp. No. Physical Date No M.p. I-118 1.23(6H, s), 1.45(6H, t, J=7.4), 2.63(3H, s), 2.67(2H, s), 4.08(2H, q, J=7.0), 4.55(2H, s), 6.57-6.63(2H, m), 6.85(1H, d, J=7.9). I-119 116-118° C. 1.24(6H, s), 2.37(3H, s), 2.64(3H, s), 2.66(2H, s), 3.84(3H, s), 4.54(2H, s), 6.75-6.80(2H, m), 6.88(1H, m). I-120  92-93° C. 1.23(6H, s), 2.27(3H, s), 2.63(3H, s), 2.67(2H, s), 3.84(3H, s), 4.51(2H, s), 6.51-6.58(2H, m), 7.10(1H, d, J=7.9). I-121 129-130° C. 1.22(6H, s), 2.30(3H, s), 2.63(3H, s), 2.65(2H, s), 3.80(3H, s), 4.53(2H, s), 6.78-6.95(3H, m). I-122  93-95° C. 1.22(6H, s), 2.12(3H, s), 2.30(3H, s), 2.64(3H, s), 2.65(2H, s), 4.51(2H, s), 6.76(1H, d, J=7.9), 6.98(1H, d, J=7.9), 7.08(1H, t, J=7.9). I-123 151-152° C. 1.22(6H, s), 1.83(3H, s), 2.63(3H, s), 2.65(2H, s), 3.17(3H, s), 4.40(1H, d, J=13.6), 4.65(1H, d, J=13.6), 7.01(1H, d, J=7.9), 7.10-7.15(2H, m), 7.30-7.35(1H, m).

TABLE 25 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-124 105-106° C.  1.23(6H, s), 1.41(3H, t, J=7.0), 2.63(3H, s), 2.66(2H, s), 4.08(2H, q, J=7.0), 4.50(2H, s), 6.88(2H, d, J=8.6), 6.98(2H, d, J=8.6). I-125 92-94° C. 1.23(6H, s), 1.40(3H, t, J=7.0), 2.62(3H, s), 2.66(2H, s), 4.08(2H, q, J=7.0), 4.50(2H, s), 6.57-6.63(2H, m), 6.70-6.75(1H, m), 7.25-7.30(1H, m). I-126 108-109° C.  1.23(6H, s), 2.63(3H, s), 2.65(2H, s), 3.81(3H, s), 4.50(2H, s), 6.92(2H, d, J=8.6), 7.04(2H, d, J=8.6). I-127 62-64° C. 1.23(6H, s), 2.63(3H, s), 2.66(2H, s), 3.82(3H, s), 4.50(2H, s), 6.57-6.63(2H, m), 6.70-6.75(1H, m), 7.25-7.30(1H, m). I-128 78-79° C. 1.23(6H, s), 1.44(3H, t, J=7.0), 2.59(3H, s), 2.63(2H, s), 3.82(3H, s), 4.10(2H, q, J=7.0), 4.47(2H, s), 6.57-6.63(2H, m), 6.82-6.87(1H, m). I-129 58-60° C. 1.04(3H, t, J=7.0), 1.23(6H, s), 2.00(2H, sext, J=7.0), 2.63(3H, s), 2.67(2H, s), 3.87(3H, s), 4.10(2H, t, J=7.0), 4.50(2H, s), 6.58-6.64(2H, m), 6.86-6.91(1H, m). I-130 1.13(6H, s), 1.45(6H, t, J=7.4), 2.28(3H, s), 2.62(2H, s), 3.74(2H, s), 4.08(4H, q, J=7.4), 6.46-6.53(2H, m), 6.88-6.92(1H, m). I-131 91-93° C. 1.04(3H, t, J=7.0), 1.22(6H, s), 1.76(2H, sext, J=7.0), 2.63(3H, s), 2.65(2H, s), 3.91(2H, t, J=7.0), 4.50(2H, s), 6.90(2H, d, J=8.6), 6.98(2H, d, J=8.6). I-132 103-104° C.  1.04(3H, t, J=7.0), 1.22(6H, s), 1.76(2H, sext, J=7.0), 2.63(3H, s), 2.65(2H, s), 3.91(2H, t, J=7.0), 4.50(2H, s), 6.50(1H, d, J=2.1), 6.60(1H, d, J=7.4), 6.72(1H, dd, J=7.4, 2.1), 7.28(1H, d, J=7.4). I-133 91-92° C. 0.98(3H, t, J=7.0), 1.23(6H, s), 1.42-1.48(2H, m), 1.70-1.80(2H, m), 2.63(3H, s), 2.65(2H, s), 3.96(2H, t, J=7.0), 4.50(2H, s), 6.90(2H, d, J=8.6), 6.98(2H, d, J=8.6). I-134 86-87° C. 0.98(3H, t, J=7.0), 1.23(6H, s), 1.42-1.48(2H, m), 1.70-1.80(2H, m), 2.63(3H, s), 2.65(2H, s), 3.96(2H, t, J=7.0), 4.50(2H, s), 6.50(1H, d, J=2.1), 6.60(1H, d, J=7.8), 6.72(1H, dd, J=7.8, 2.1), 7.28(1H, d, J=7.8).

TABLE 26 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-135 69-70° C. 1.22(6H, s), 1.47(3H, t, J=7.0), 2.64(3H, s), 2.66(2H, s), 3.88(3H, s), 4.15(2H, q, J=7.0), 4.51(2H, s), 6.61(1H, d, J=8.2), 6.62(1H, d, J=2.1), 6.88(1H, d, J=8.2). I-136 88-89° C. 1.04(3H, t, J=7.0), 1.23(6H, s), 1.80(2H, sext, J=7.0), 2.63(3H, s), 2.67(2H, s), 3.87(3H, s), 3.90(2H, t, J=7.0), 4.51(2H, s), 6.61(1H, dd, J=8.2, 2.1), 6.62(1H, d, J=2.1), 6.88(1H, d, J=8.2). I-137 83-85° C. 0.98(3H, t, J=7.0), 1.23(6H, s), 1.42-1.48(2H, m), 1.70-1.80(2H, m), 2.64(3H, s), 2.68(2H, s), 3.87(3H, s), 4.03(2H, t, J=7.0), 4.50(2H, s), 6.59(1H, d, J=8.2), 6.61(1H, s), 6.88(1H, d, J=8.2). I-138 84-85° C. 1.23(6H, s), 1.34(6H, d, J=6.1), 2.63(3H, s), 2.65(2H, s), 4.50(2H, s), 4.53(1H, sept, J=6.1), 6.89(2H, d, J=8.6), 7.04(2H, d, J=8.6). I-139 92-93° C. 1.23(6H, s), 1.34(6H, d, J=6.1), 2.63(3H, s), 2.65(2H, s), 4.50(2H, s), 4.53(1H, sept, J=6.1), 6.50(1H, d, J=2.1), 6.60(1H, d, J=8.0), 6.72(1H, dd, J=8.0, 2.1), 7.28(1H, d, J=8.0). I-140 109-110° C.  1.22(6H, s), 2.63(3H, s), 2.65(2H, s), 4.50(2H, s), 7.04(2H, d, J=7.5), 7.15(1H, d, J=7.5), 7.32(2H, t, J=7.5). I-141 92-93° C. 1.23(6H, s), 2.63(3H, s), 2.69(2H, s), 4.54(2H, s), 7.01-7.08(1H, m), 7.11-7.15(3H, m). I-142 133-135° C.  1.23(6H, s), 2.63(3H, s), 2.69(2H, s), 4.54(2H, s), 7.03(1H, dd, J=8.0, 2.1), 7.08(1H, dd, J=8.0, 2.1), 7.25(1H, t, J=8.0), 7.44(1H, t, J=8.0). I-143 92-93° C. 1.23(6H, s), 2.63(3H, s), 2.67(2H, s), 4.50(2H, s), 6.88(1H, dd, J=8.0, 2.1), 7.03(1H, d, J=2.1), 7.15(1H, dd, J=8.0, 2.1), 7.28(1H, t, J=8.0). I-144 134-135° C.  1.22(6H, s), 2.22(3H, s), 2.63(3H, s), 2.65(2H, s), 4.50(2H, s), 7.00(1H, d, J=8.1), 7.08(1H, t, J=8.1), 7.15-7.25(2H, m). I-145 87-89° C. 1.23(6H, s), 2.37(3H, s), 2.63(3H, s), 2.66(2H, s), 4.50(2H, s), 6.82(1H, d, J=8.1), 6.84(1H, s), 6.98(1H, d, J=8.1), 7.21(1H, t, J=8.1).

TABLE 27 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-146  91-93° C. 1.23(6H, s), 2.35(3H, s), 2.63(3H, s), 2.65(2H, s), 4.50(2H, s), 6.92(2H, d, J=8.6), 7.15(2H, d, J=8.6). I-147  82-83° C. 0.90(3H, t, J=7.0), 1.22(6H, s), 1.28-1.40(2H, m), 1.48-1.55(2H, m), 2.55(2H, t, J=7.0), 2.64(3H, s), 2.66(2H, s), 4.50(2H, s), 6.90(1H, d, J=7.8), 7.09(1H, t, J=7.8), 7.11(1H, t, J=7.8), 7.28(1H, d, J=7.8). I-148  72-73° C. 0.90(3H, t, J=7.0), 1.22(6H, s), 1.28-1.40(2H, m), 1.48-1.55(2H, m), 2.60(2H, t, J=7.0), 2.64(3H, s), 2.66(2H, s), 4.50(2H, s), 6.95(2H, d, J=8.6), 7.18(2H, d, J=8.6) I-149 133-134° C. 1.23(6H, s), 1.35(9H, s), 2.65(3H, s), 2.69(2H, s), 4.50(2H, s), 6.97(1H, d, J=7.8), 7.13(1H, t, J=7.8), 7.19(1H, t, J=7.8), 7.41(1H, d, J=7.8). I-150  99-100° C. 1.22(6H, s), 1.23(3H, t, J=7.4), 2.62(3H, s), 2.64(2H, s), 2.66(2H, q, J=7.4), 4.50(2H, s), 6.95(2H, d, J=8.6), 7.20(2H, d, J=8.6). I-151  40-42° C. 1.23(6H, s), 1.24(3H, t, J=7.0), 2.64(3H, s), 2.66(2H, s), 2.67(2H, q, J=7.0), 4.52(2H, s), 6.83(1H, d, J=8.1), 6.86(1H, s), 7.00(1H, d, J=8.1), 7.28(1H, t, J=8.1). I-152 118-119° C. 1.23(6H, s), 2.64(3H, s), 2.67(2H, s), 4.52(2H, s), 6.97-7.10(4H, m). I-153  89-90° C. 1.23(6H, s), 2.64(3H, s), 2.67(2H, s), 4.52(2H, s), 6.73-6.90(3H, m), 7.25-7.30(1H, m). I-154 111-112° C. 1.22(6H, s), 1.25(6H, d, J=7.0), 2.62(3H, s), 2.64(2H, s), 2.91(1H, sept, J=7.0), 4.50(2H, s), 6.95(2H, d, J=8.6), 7.25(2H, d, J=8.6). I-155 127-129° C. 1.23(6H, s), 2.62(3H, s), 2.64(2H, s), 3.14-3.18(4H, m), 3.85-3.90(4H, m), 4.50(2H, s), 6.93(2H, d, J=8.6), 7.04(2H, d, J=8.6). I-156  91-93° C. 1.24(6H, s), 2.62(3H, s), 2.65(3H, s), 2.68(2H, s), 4.53(2H, s), 7.21-7.25(1H, m), 7.48(1H, t, J=7.9), 7.61(1H, t, J=1.8), 7.74-7.78(1H, m).

TABLE 28 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-157 103.5-104.5° C. 1.23(6H, s), 2.63(3H, s), 2.68(2H, s), 4.50(2H, s), 6.88-6.94(2H, m), 7.46-7.51(2H, m). I-158     97-98° C. 1.23(6H, s), 2.64(3H, s), 2.68(2H, s), 4.51(2H, s), 6.93-6.97(1H, m), 7.19-7.31(3H, m). I-159 155.5-156.5° C. 1.24(6H, s), 2.65(3H, s), 2.69(2H, s), 4.54(2H, s), 6.98-7.05(2H, m), 7.28-7.34(1H, m), 7.59-7.63(1H, m). I-160    102-106° C. 1.23(6H, s), 2.23(3H, s), 2.64(3H, s), 2.67(2H, s), 4.00(3H, s), 4.52(2H, s), 7.01-7.05(1H, m), 7.28(1H, t, J=1.8), 7.37(1H, t, J=7.8), 7.45-7.49(1H, m). I-161    111-112° C. 1.23(6H, s), 2.60(3H, s), 2.65(3H, s), 2.69(2H, s), 4.53(2H, s), 7.06-7.10(2H, m), 7.97-8.03(2H, m). I-162    124-125° C. 1.23(6H, s), 2.23(3H, s), 2.64(3H, s), 2.67(2H, s), 4.00(3H, s), 4.52(2H, s), 7.00-7.05(2H, m), 7.65-7.70(2H, m). I-163   102-103.5° C. 1.23(6H, s), 1.32(6H, d, J=6.3), 2.63(2H, s), 2.64(3H, s), 4.52(2H, s), 4.52(1H, sept, J=6.3), 6.90-6.98(3H, m), 7.04-7.13(1H, m) I-164     90-92° C. 0.94(3H, t, J=7.3), 1.23(6H, s), 1.58(2H, sext, J=7.3), 2.51-2.56(2H, m), 2.65(3H, s), 2.65(2H, s), 4.51(2H, s), 6.90(1H, dd, J=7.6, 1.3), 7.07-7.25(3H, m) I-165    157-158° C. 1.23(6H, s), 2.64(3H, s), 2.68(2H, s), 4.49(2H, s), 7.08(1H, d, J=7.9), 7.22(1H, d, J=7.6), 7.50-7.56(1H, m), 7.66-7.69(1H, m) I-166    145-146° C. 1.24(6H, s), 2.64(3H, s), 2.69(2H, s), 4.51(2H, s), 7.00-7.13(7H, m), 7.30-7.37(2H, m) I-167     77-79° C. 0.95(3H, t, J=7.3), 1.23(6H, s), 1.65(2H, sext, J=7.3), 2.58(2H, t, J=7.3), 2.63(3H, s), 2.66(2H, s), 4.51(2H, s), 6.93-7.00(2H, m), 7.14-7.20(2H, m)

TABLE 29 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-168 117-118° C. 1.23(6H, s), 1.55(9H, s), 2.63(3H, s), 2.67(2H, s), 4.52(2H, s), 6.96-7.01(2H, m), 7.37-7.42(2H, m). I-169  55-56° C. 1.24(6H, s), 2.65(3H, s), 2.69(2H, s), 4.53(2H, s), 7.19(1H, d, J=7.6), 7.26-7.27(1H, m), 7.40-7.52(2H, m). I-170  88-90° C. 1.24(6H, s), 2.65(3H, s), 2.69(2H, s), 4.53(2H, s), 7.10(2H, d, J=8.2), 7.63(2H, d, J=8.2). I-171 1.15(6H, s), 1.18(6H, d, J=6.9), 2.17(3H, s), 2.31(3H, s), 2.64(2H, s), 3.11(1H, sept, J=6.9), 3.78(2H, s), 6.80(1H, d, J=8.2), 7.11-7.18(1H, m), 7.28-7.35(1H, m). I-172 1.15(6H, s), 1.18(6H, d, J=6.9), 2.15(3H, s), 2.31(3H, s), 2.65(2H, s), 3.11(1H, sept, J=6.9), 3.78(2H, s), 6.99(1H, s), 7.11-7.18(1H, m), 7.28-7.35(1H, s). I-173 121-123° C. 1.22(6H, s), 2.64(3H, s), 2.67(2H, s), 3.89(3H, s), s), 4.54(2H, s), 6.96(1H, d, J=8.6), 7.67(1H, d, 3.89(3H, J=2.1), 7.87(1H, dd, J=8.6, 2.1). I-174 146-147° C. 1.24(6H, s), 2.59(2H, s), 2.65(3H, s), 2.96-2.99(4H, m), 3.76-3.79(4H, m), 4.52(2H, s), 6.98-7.17(4H, m). I-175 155-157° C. 1.23(6H, s), 2.64(3H, s), 2.66(2H, s), 3.16-3.20(4H, m), 3.84-3.88(4H, m), 4.51(2H, s), 6.54-6.57(2H, m), 6.70-6.74(1H, m), 7.24-7.30(1H, m). I-176 1.22(6H, d, J=6.6), 1.23(6H, s), 1.38(3H, t, J=7.1), 2.65(3H, s), 2.67(2H, s), 3.08-3.18(1H, m), 4.37(2H, q, J=6.9), 4.52(2H, s), 7.38(1H, d, J=7.9), 7.59(1H, d, J=2.0), 7.82(1H, dd, J=8.1, 1.8). I-177 120-122° C. 1.23(6H, s), 1.50-1.61(2H, m), 1.67-1.75(4H, m), 2.62(3H, s), 2.66(2H, s), 3.13-3.17(4H, m), 4.50(2H, s), 6.92-7.02(4H, m). I-178 124-125° C. 1.23(6H, s), 1.85-1.90(4H, m), 2.62(3H, s), 2.68(2H, s), 3.22-3.27(4H, m), 4.48(2H, s), 6.74-6.80(2H, m), 6.95-6.98(1H, m), 7.03-7.10(1H, m).

TABLE 30 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-179 1.23(6H, s), 2.50(3H, s), 2.64(3H, s), 2.67(2H, s), 4.51(2H, s), 6.78-6.82(1H, m), 6.91(1H, t, J=2.0), 7.03-7.07(1H, m), 7.25-7.31(1H, m). I-180 102-103° C. 1.23(6H, s), 2.49(3H, s), 2.63(3H, s), 2.67(2H, s), 4.51(2H, s), 6.96-7.01(2H, m), 7.27-7.31(2H, m). I-181  82-83° C. 1.23(6H, s), 2.64(3H, s), 2.67(2H, s), 4.52(2H, s), 7.07(1H, dd, J=7.6, 1.7), 7.14-7.20(1H, m), 7.25-7.34(2H, m). I-182 1.23(6H, s), 2.64(3H, s), 2.69(2H, s), 4.52(2H, s), 6.90(1H, s), 6.93-7.04(2H, m), 7.38(1H, t, J=8.2) I-183  68-70° C. 1.24(6H, s), 2.64(3H, s), 2.69(2H, s), 4.51(2H, s), 7.01-7.07(2H, m), 7.21-7.24(2H, m). I-184 169-170° C. 1.25(6H, s), 2.66(3H, s), 2.70(2H, s), 4.54(2H, s), 7.13-7.18(2H, m), 7.34-7.39(1H, m), 7.59-7.63(2H, m), 7.86-7.91(1H, m), 8.58(1H, dd, J=4.8, 1.6), 8.87(1H, t, J=1.5) I-185 92.5-93.5° C.   1.24(6H, s), 2.65(3H, s), 2.69(2H, s), 4.54(2H, s), 7.05-7.09(1H, m), 7.24(1H, t, J=1.6), 7.34-7.40(2H, m), 7.49(1H, t, J=7.6), 7.87-7.9(1H, m), 8.60(1H, dd, J=4.9, 1.4), 8.87(1H, dd, J=2.3, 0.7) I-186 1.09(6H, s), 2.56(3H, s), 2.58(2H, s), 4.20(2H, s), 7.09-7.12(1H, m), 7.24-7.30(2H, m), 7.36-7.45(2H, m), 7.75-7.79(1H, m), 8.54(1H, dd, J=4.9, 1.6), 8.68(1H, dd, J=2.3, 0.7) I-187 110.5-111.5° C.    1.17(6H, s), 2.51(3H, s), 2.61(2H, s), 4.33(2H, s), 6.93-7.19(7H, m), 7.23-7.30(2H, m) I-188  75-76° C. 1.14(6H, s), 1.43(6H, t, J=7.4), 2.61(2H, s), 3.65(2H, s), 3.84(3H, s), 4.08(4H, q, J=7.4), 6.46(1H, dd, J=8.1, 2.2), 6.52(1H, d, J=2.2), 6.84(1H, d, J=8.4). I-189 1.19(6H, s), 2.61(2H, s), 3.65(2H, s), 3.85(3H, s), 3.88(3H, s), 6.85-6.99(3H, m), 7.02-7.15(1H, m).

TABLE 31 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-190 1.13(6H, s), 1.23(3H, t, J=7.4), 2.62(2H, s), 2.66(2H, q, J=7.4), 3.64(2H, s), 3.84(3H, s), 6.84(2H, d, J=8.6), 7.16(2H, d, J=8.6). I-191 45-47° C. 1.14(6H, s), 1.25(6H, d, J=7.0), 2.62(2H, s), 2.91(1H, sept, J=7.0), 3.64(2H, s), 3.84(3H, s), 6.86(2H, d, J=8.6), 7.19(2H, d, J=8.6). I-192 93-95° C. 1.15(6H, s), 2.31(3H, s), 2.62(2H, s), 3.80(2H, s), 3.85(3H, s), 6.85-6.99(3H, m), 7.02-7.15(1H, m). I-193 65-67° C. 1.13(6H, s), 1.23(3H, t, J=7.4), 2.31(3H, s), 2.62(2H, s), 2.65(2H, q, J=7.4), 3.77(2H, s), 6.90(2H, d, J=8.3), 7.21(2H, d, J=8.3). I-194 95-97° C. 1.15(6H, s), 1.24(6H, d, J=7.0), 2.31(3H, s), 2.64(2H, s), 2.91(1H, sept, J=7.0), 3.77(2H, s), 6.90(2H, d, J=8.6), 7.21(2H, d, J=8.6). I-195 94-96° C. 1.15(6H, s), 1.41(3H, t, J=7.0), 2.31(3H, s), 2.64(2H, s), 3.77(2H, s), 4.05(2H, q, J=7.4), 6.90-6.99(4H, m). I-196 99-100° C.  1.15(6H, s), 1.47(3H, t, J=7.0), 2.32(3H, s), 2.66(2H, s), 3.77(2H, s), 3.88(3H, s), 4.08(2H, q, J=7.0), 6.52(1H, d, J=8.2), 6.56(1H, d, J=2.1), 6.88(1H, d, J=8.2). I-197 133-134° C.  1.23(6H, s), 1.50-1.75(6H, m), 2.63(3H, s), 2.65(2H, s), 3.18(4H, t, J=5.4), 4.51(2H, s), 6.47-6.57(2H, m), 6.72-6.76(1H, m), 7.21(1H, d, J=8.1) I-198 124-125° C.  1.17(6H, t, J=6.9), 1.23(6H, s), 2.61(3H, s), 2.68(2H, s), 3.35(4H, q, J=6.9), 4.49(2H, s), 6.68(2H, d, J=8.9), 7.04(2H, d, J=8.9) I-199 85-87° C. 1.22(6H, s), 2.63(3H, s), 2.67(2H, s), 3.89(3H, s), 3.92(3H, s), 4.54(2H, s), 7.01(1H, d, J=7.9), 7.62(1H, d, J=1.3), 7.67(1H, dd, J=7.9, 1.7) I-200 137-138° C.  1.23(6H, s), 2.11-2.22(2H, m), 2.62(2H, t, J=7.9), 2.64(3H, s), 2.67(2H, s), 3.88(2H, t, J=7.1), 4.52(2H, s), 6.81-6.84(1H, m), 7.30-7.50(3H, m)

TABLE 32 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-201 86.5-87.5° C.   1.22(6H, s), 2.62(3H, s), 2.67(2H, s), 4.50(2H, s), 6.71(1H, t, J=2.0), 6.76-6.82(2H, m), 7.02-7.13(3H, m), 7.29-7.37(3H, m) I-202 162-163° C. 1.25(6H, s), 2.65(3H, s), 2.70(2H, s), 4.54(2H, s), 7.10-7.14(2H, m), 7.33-7.46(3H, m), 7.59-7.63(4H, m) I-203 56.5-57.5° C.   1.06(6H, s), 2.51(3H, s), 2.59(2H, s), 4.14(2H, s), 7.07(1H, dd, J=8.2, 1.3), 7.21-7.45(8H, m) I-204  97-99° C. 1.24(6H, s), 2.65(3H, s), 2.68(2H, s), 4.54(2H, s), 7.00-7.04(1H, m), 7.25-7.26(1H, m), 7.33-7.48(5H, m), 7.60-7.63(2H, m) I-205  95-96° C. 1.21(6H, s), 1.21(6H, d, J=6.9), 2.61(2H, s), 4.13(3H, s), 4.16(2H, s), 6.77-6.81(1H, m), 7.13-7.16(2H, m), 7.29-7.33(1H, m) I-206 128-129° C. 1.18(6H, d, J=6.9), 1.22(6H, s), 2.63(3H, s), 2.66(2H, s), 2.96-3.06(1H, m), 4.48(2H, s), 6.67(1H, d, J=8.2), 7.47(1H, dd, J=8.2, 1.7), 7.59(1H, d, J=2.0) I-207 149-150° C. 1.23(6H, s), 2.63(3H, s), 2.67(2H, s), 3.71(8H, m), 3.86(3H, s), 4.53(2H, s), 6.95-7.05(3H, m) I-208 124-126° C. 1.23(6H, s), 2.61(3H, s), 2.67(2H, s), 2.96(6H, s), 4.50(2H, s), 6.74(2H, d, J=8.2), 7.04(2H, d, J=8.2). I-209 107-109° C. 1.23(6H, s), 2.63(3H, s), 2.65(2H, s), 2.96(6H, s), 4.51(2H, s), 6.34(1H, d, J=2.0), 6.38(1H, d, J=8.0), 6.54(1H, dd, J=8.0, 2.0), 7.24(2H, d, J=8.0). I-210  98-99° C. 1.06(3H, t, J=7.4), 1.23(6H, s), 2.63(5H, s), 2.65(3H, s), 2.99(2H, q, J=7.4), 4.51(2H, s), 6.98-7.10(3H, m), 7.15-7.20(1H, m). I-211  94-96° C. 0.84(3H, t, J=7.4), 1.22(6H, s), 1.49(2H, sext, J=7.3), 2.63(3H, s), 2.65(2H, s), 2.72(3H, s), 2.84(2H, t, J=7.4), 4.51(2H, s), 6.90-7.05(3H, m), 7.10-715(1H, m).

TABLE 33 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-212 98-99° C. 1.02(6H, t, J=7.4), 1.22(6H, s), 2.61(2H, s), 2.63(3H, s), 3.06(4H, q, J=7.4), 4.51(2H, s), 6.98-7.10(4H, m). I-213 83-84° C. 1.23(6H, s), 2.64(3H, s), 2.71(2H, s), 4.57(2H, s), 6.90-7.12(3H, m) I-214 1.19(6H, d, J=6.9), 1.23(6H, s), 2.64(3H, s), 2.67(2H, s), 3.06(1H, sept, J=6.9), 4.49(2H, s), 6.85(1H, d, J=8.2), 7.14(1H, dd, J=8.2, 2.3), 7.27(1H, d, J=2.3) I-215 83-85° C. 1.23(6H, s), 2.32(3H, s), 2.63(3H, s), 2.66(2H, s), 2.71(6H, s), 4.50(2H, s), 6.75-6.80(1H, m), 6.98(1H, s), 6.97-7.00(1H, m). I-216 99-100° C.  1.23(6H, s), 2.33(3H, s), 2.62(3H, s), 2.65(2H, s), 2.70(6H, s), 4.50(2H, s), 6.78(2H, t, J=7.9), 6.91(1H, d, J=7.9). I-217 98-99° C. 1.23(6H, s), 2.30(3H, s), 2.63(3H, s), 2.64(2H, s), 2.67(6H, s), 4.50(2H, s), 6.81(1H, s), 6.92(2H, s). I-218 117-19° C.  1.23(6H, s), 2.63(3H, s), 2.65(2H, s), 2.68(6H, s), 4.50(2H, s), 6.89(1H, d, J=8.5), 6.99(1H, d, J=2.0), 7.04(1H, dd, J=7.9, 2.0). I-219 68-70° C. 1.22(6H, s), 2.22(6H, s), 2.64(3H, s), 2.66(2H, s), 4.54(2H, s), 6.93-6.98(1H, m), 7.04(2H, d, J=8.0). I-220 97-99° C. 1.22(6H, s), 1.34(3H, t, J=7.4), 2.64(2H, s), 2.72(6H, s), 3.25(2H, q, J=7.4), 4.47(2H, s), 6.94-7.05(3H, m), 7.15-7.20(1H, m). I-221 118-119° C.  1.22(6H, s), 1.34(3H, t, J=7.4), 2.64(2H, s), 2.95(6H, s), 3.25(2H, q, J=7.4), 4.47(2H, s), 6.34(1H, d, J=7.5), 6.38(1H, s), 6.52(1H, d, J=7.5), 7.24(1H, t, J=7.5). I-222 74-76° C. 1.22(6H, s), 1.34(3H, t, J=7.4), 2.33(3H, s), 2.63(2H, s), 2.70(6H, s), 3.25(2H, q, J=7.4), 4.47(2H, s), 6.78(1H, d, J=7.5), 6.82(1H, s), 6.91(1H, t, J=7.5).

TABLE 34 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-223 1.22(6H, s), 1.25(6H, d, J=7.0), 1.34(3H, t, J=7.4), 2.65(2H, s), 2.91(1H, sept, J=7.0), 3.25(2H, q, J=7.4), 4.50(2H, s), 6.98(2H, d, J=8.2), 7.28(2H, d, J=8.2). I-224 1.21(6H, s), 2.62(3H, s), 2.66(2H, s), 2.97(3H, d, J=4.9), 3.84(3H, s), 4.51(2H, s), 6.66(1H, brs), 6.96(1H, d, J=7.9), 7.30-7.33(1H, m), 7.49(1H, d, J=1.3) I-225 69-71° C. 1.23(6H, s), 2.64(3H, s), 2.68(2H, s), 4.52(2H, s), 6.49(1H, t, J=74.6), 7.04-7.26(4H, m) I-226 1.23(6H, s), 2.64(3H, s), 2.68(2H, s), 4.51(2H, s), 6.50(1H, t, J=74.2), 7.00-7.05(2H, s), 7.11-7.16(2H, m) I-227 81-83° C. 1.17(6H, t, J=7.0), 1.23(6H, s), 2.63(3H, s), 2.66(2H, s), 3.35(4H, q, J=7.0), 4.52(2H, s), 6.29(1H, s), 6.30(1H, dt, J=8.2, 2.3), 6.49(1H, dd, J=8.2, 2.3), 7.19(1H, t, J=8.2). I-228 106-107° C.  1.21(6H, s), 2.61(3H, s), 2.64(2H, s), 2.70(6H, s), 4.47(2H, s), 6.90(2H, s), 6.93(1H, s). I-229 121-122° C.  1.23(6H, s), 2.62(3H, s), 2.65(2H, s), 2.70(6H, s), 4.48(2H, s), 6.50-6.70(2H, m), 6.93(1H, dd, J=8.5, 6.2). I-230 85-86° C. 1.21(6H, s), 2.63(3H, s), 2.64(2H, s), 2.66(6H, s), 4.49(2H, s), 6.74-6.79(2H, m), 6.93-6.98(1H, m). I-231 82-84° C. 1.23(6H, s), 1.25(3H, t, J=7.6), 2.62(3H, s), 2.66(2H, s), 2.67(2H, q, J=7.6), 2.71(6H, s), 4.50(2H, s), 6.80(1H, d, J=7.6), 6.84(1H, s), 6.93(1H, d, J=7.6). I-232 75-76° C. 1.22(3H, t, J=7.6), 1.23(6H, s), 2.60(2H, q, J=7.6), 2.63(3H, s), 2.64(2H, s), 2.68(6H, s), 4.50(2H, s), 6.83(1H, s), 6.93(2H, s). I-233 86-88° C. 1.22(6H, s), 1.33(3H, t, J=7.4), 2.64(2H, s), 2.71(6H, s), 3.24(2H, q, J=7.4), 4.47(2H, s), 6.92(2H, s), 6.94(1H, s).

TABLE 35 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-234 70-71° C. 1.22(6H, s), 1.34(3H, t, J=7.4), 2.64(2H, s), 2.71(6H, s), 3.25(2H, q, J=7.4), 4.46(2H, s), 6.60-6.68(2H, m), 6.92-6.94(1H, m). I-235 80-82° C. 1.22(6H, s), 1.24(3H, t, J=7.6), 1.33(3H, t, J=7.4), 2.60(2H, q, J=7.6), 2.61(2H, s), 2.71(6H, s), 3.24(2H, q, J=7.4), 4.47(2H, s), 6.81(1H, d, J=7.6), 6.94(1H, s), 6.94(1H, d, J=7.6). I-236 1.03(3H, t, J=7.3), 1.20(6H, d, J=6.9), 1.23(6H, s), 1.40(3H, d, J=6.9), 1.61-1.89(2H, m), 2.63(2H, s), 3.15(1H, sept, J=6.9), 3.95(1H, q, J=6.9), 4.47(2H, s), 6.89-6.92(1H, m), 7.13-7.20(2H, m), 7.31-7.34(1H, m) I-237 1.05(6H, d, J=6.6), 1.21(6H, d, J=6.6), 1.23(6H, s), 1.98-2.08(1H, m), 2.64(2H, s), 3.16(1H, sept, J=6.6), 3.20(2H, d, J=6.6), 4.49(2H, s), 6.88-6.92(1H, m), 7.13-7.22(2H, m), 7.30-7.35(1H, m) I-238 102-104° C. 1.20(6H, d, J=6.9), 1.22(6H, s), 2.61(2H, s), 2.85-2.95(1H, m), 3.19(3H, d, J=4.6), 4.46(2H, s), 6.73-6.79(1H, m), 7.14-7.20(2H, m), 7.29-7.34(1H, m), 12.40(1H, brs) I-239 58-60° C. 1.23(6H, s), 2.17(3H, s), 2.64(3H, s), 2.65(2H, s), 2.70(6H, s), 4.52(2H, s), 6.63(1H, d, J=7.9), 6.87(1H, d, J=7.9), 7.14(1H, d, J=7.9). I-240 100-101° C. 1.23(6H, s), 2.62(3H, s), 2.64(2H, s), 2.78(6H, s), 3.89(3H, s), 4.52(2H, s), 6.60-6.70(2H, m), 6.94(1H, d, J=7.9). I-241 82-83° C. 1.23(6H, s), 2.30(3H, s), 2.63(3H, s), 2.65(2H, s), 2.70(6H, s), 4.52(2H, s), 6.63(1H, dt, J=7.9, 1.9), 6.70(1H, d, J=1.9), 7.14(1H, d, J=7.9). I-242  99-100° C. 1.23(6H, s), 2.63(3H, s), 2.68(2H, s), 2.81(6H, s), 4.50(2H, s), 6.91(1H, dt, J=8.4, 2.6), 7.06(1H, d, J=8.4), 7.14(1H, d, J=2.6). I-243 63-64° C. 1.23(6H, s), 2.63(3H, s), 2.67(2H, s), 2.78(6H, s), 3.89(3H, s), 4.52(2H, s), 6.67(1H, s), 6.70(1H, d, J=7.9), 6.81(1H, d, J=7.9). I-244 68-70° C. 0.88(6H, t, J=7.5), 1.22(6H, d, J=6.9), 1.35(3H, t, J=7.4), 1.50-1.70(4H, m), 2.61(2H, s), 3.15(1H, sept, J=6.9), 3.29(2H, q, J=7.4), 4.44(2H, s), 6.89-6.92(1H, m), 7.08-7.21(2H, m), 7.30-7.35(1H, m).

TABLE 36 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-245 81-82° C. 1.14(6H, s), 1.20(6H, d, J=6.9), 2.63(2H, s), 3.06(2H, s), 3.08(1H, sept, J=6.9), 3.18(3H, s), 6.74(1H, dd, J=7.3, 1.7), 6.98-7.10(2H, m), 7.20-7.24(1H, m) I-246 47-49° C. 0.95(3H, t, J=7.3), 1.13(6H, s), 1.20(6H, d, J=6.9), 1.55-1.74(2H, m), 2.62(2H, s), 3.03-3.11(3H, m), 3.52-3.57(2H, m), 6.73(1H, dd, J=7.6, 1.7), 6.96-7.10(2H, m), 7.21(1H, dd, J=7.3, 1.7) I-247 68-70° C. 1.11(6H, s), 1.18(6H, d, J=6.9), 1.19(6H, d, J=6.9), 2.56(2H, s), 2.89(2H, s), 3.08(1H, sept, J=6.9), 5.08(1H, sept, J=6.9), 6.73(1H, dd, J=7.9, 1.7), 6.99-7.10(2H, m), 7.21(1H, dd, J=7.9, 1.7) I-248 0.97(6H, d, J=6.9), 1.14(6H, s), 1.18(6H, d, J=6.9), 2.05-2.15(1H, m), 2.62(2H, s), 3.07(2H, s), 3.08(1H, sept, J=6.9), 3.44(2H, d, J=7.6), 6.71(1H, dd, J=7.6, 1.7), 6.96-7.09(2H, m), 7.21(1H, dd, J=7.6, 1.7) I-249 96-97° C. 1.23(6H, s), 2.64(3H, s), 2.68(2H, s), 4.59(2H, s), 7.04(1H, d, J=7.3), 7.41-7.50(3H, m), 7.67(1H, d, J=7.3), 7.87(1H, dd, J=7.3, 2.1), 8.05(1H, d, J=7.3). I-250 108-109° C. 1.24(6H, s), 2.67(3H, s), 2.69(2H, s), 4.59(2H, s), 7.15(1H, d, J=7.3), 7.41(1H, q, J=7.3), 7.69(1H, t, J=8.4), 7.91(1H, d, J=7.3), 8.45(1H, d, J=8.4), 8.92-8.95(1H, m). I-251 105-107° C. 1.22(6H, s), 2.62(3H, s), 2.65(2H, s), 3.97(3H, s), 4.53(2H, s), 6.87-6.90(1H, m), 7.25-7.30(1H, m), 7.96-7.99(1H, m). I-252 132-133° C. 1.23(6H, s), 2.63(3H, s), 2.68(2H, s), 2.92(3H, s), 4.49(2H, s), 6.73-6.78(1H, m), 7.20-7.23(1H, m), 8.05-8.07(1H, m) I-253 118-120° C. 1.23(6H, s), 2.60(3H, s), 2.63(2H, s), 4.52(2H, s), 7.30(2H, s), 8.12(1H, s). I-254 112-113° C. 1.23(6H, s), 2.63(3H, s), 2.69(2H, s), 3.94(3H, s), 4.51(2H, s), 6.76(1H, d, J=8.1), 7.35(1H, dd, J=8.1, 2.1), 7.92(1H, d, J=2.1). I-255 109-110° C. 1.23(6H, s), 1.40(3H, t, J=7.0), 2.62(3H, s), 2.66(2H, s), 4.38(2H, q, J=7.0), 4.51(2H, s), 6.75(1H, d, J=8.1). 7.35(1H, dd, J=8.1, 2.1), 7.90(1H, d, J=2.1).

TABLE 37 Physical Date No M.p. NMR(CHCl₃) I-256 75-76° C. 1.03(3H, t, J=7.6), 1.22(6H, s), 1.76(2H, sext, J=7.6), 2.63(3H, s), 2.65(2H, s), 4.24(2H, t, J=7.6), 4.51(2H, s), 6.76(1H, d, J=8.1), 7.35(1H, dd, J=8.1, 2.1), 7.92(1H, d, J=2.1). I-257 74-76° C. 1.24(6H, s), 1.36(6H, d, J=6.3), 2.63(3H, s), 2.70(2H, s), 4.51(2H, s), 5.28(1H, sept, J=6.3), 6.70(1H, d, J=8.1), 7.32(1H, dd, J=8.1, 2.1), 7.92(1H, d, J=2.1). I-258 102-104° C. 1.23(6H, s), 2.58(3H, s), 2.63(2H, s), 2.69(3H, s), 4.51(2H, s), 7.20-7.26(2H, m), 8.21(1H, d, J=2.1). I-259 81-83° C. 1.23(6H, s), 1.38(3H, t, J=7.3), 2.63(3H, s), 2.63(2H, s), 3.18(2H, q, J=7.3), 4.51(2H, s), 7.15-7.26(2H, m), 8.21(1H, d, J=2.1). I-260 78-79° C. 1.05(3H, t, J=7.4), 1.23(6H, s), 1.75(2H, sext, J=7.3), 2.63(3H, s), 2.65(2H, s), 3.15(2H, t, J=7.4), 4.51(2H, s), 7.15-7.26(2H, m), 8.20(1H, d, J=2.1). I-261 102-103° C. 1.23(6H, s), 1.40(6H, d, J=6.6), 2.63(3H, s), 2.66(2H, s), 4.00(1H, sept, J=6.6), 4.51(2H, s), 7.15-7.26(2H, m), 8.22(1H, d, J=2.1). I-262 109-110° C. 1.22(6H, s), 2.61(3H, s), 2.65(2H, s), 2.70(6H, s), 3.80(3H, s), 4.48(2H, s), 6.47(1H, dd, J=7.9, 2.1), 6.56(1H, d, J=2.1), 6.95(1H, d, J=7.9). I-263 99-100° C. 1.22(6H, s), 2.62(3H, s), 2.63(2H, s), 2.64(6H, s), 3.78(3H, s), 4.48(2H, s), 6.59(1H, d, J=2.1), 6.64(1H, dd, J=7.9, 2.1), 6.98(1H, d, J=7.9). I-264 114-115° C. 0.98(6H, t, J=7.0), 1.23(6H, s), 2.16(3H, s), 2.63(3H, s), 2.64(2H, s), 2.98(4H, q, J=7.0), 4.52(2H, s), 6.65(1H, d, J=7.9), 6.89(1H, d, J=7.9), 7.13(1H, t, J=7.9). I-265 66-67° C. 0.98(6H, t, J=7.0), 1.23(6H, s), 2.16(3H, s), 2.63(3H, s), 2.64(2H, s), 2.98(4H, q, J=7.0), 4.52(2H, s), 6.63(1H, dd, J=7.9, 2.1), 6.70(1H, d, J=2.1), 7.16(1H, d, J=7.9). I-266 88-90° C. 1.04(6H, t, J=7.0), 1.24(6H, s), 2.63(3H, s), 2.67(2H, s), 3.17(4H, q, J=7.0), 3.86(3H, s), 4.51(2H, s), 6.67(1H, s), 6.70(1H, d, J=7.9), 6.85(1H, d, J=7.9).

TABLE 38 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-267 138-140° C. 0.82-0.92(9H, m), 1.18(3H, d, J=6.9), 1.51-1.65(6H, m), 2.62(2H, s), 2.65(3H, s), 2.87(1H, sept, J=6.9), 4.33(1H, d, J=13.5), 4.59(1H, d, J=13.5), 6.89-6.92(1H, m), 7.13-7.28(3H, m) I-268 161-163° C. 0.89-0.95(6H, m), 1.21(6H, d, J=6.9), 1.25-1.54(8H, m), 2.62(2H, s), 2.65(3H, s), 3.10(1H, sept, J=6.9), 4.47(2H, s), 6.88-6.92(1H, m), 7.14-7.18(2H, m), 7.31-7.34(1H, m) I-269 1.21(6H, d, J=6.9), 1.65-1.88(8H, m), 2.64(3H, s), 2.75(2H, s), 3.09(1H, sept, J=6.9), 4.57(2H, s), 6.90-6.94(1H, m), 7.13-7.20(2H, m), 7.30-7.35(1H, m) I-270 1.21(6H, d, J=6.9), 1.37-1.54(8H, m), 1.76-1.80(2H, m), 2.65(3H, s), 2.67(2H, s), 3.09(1H, sept, J=6.9), 4.54(2H, s), 6.89(1H, m), 7.11-7.21(2H, m), 7.29-7.34(1H, m)

TABLE 39 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-271 1.04(3H, s), 1.08(3H, s), 1.29(6H, d), J=6.9), 2.69(2H, s), 3.40(1H, sept, J=6.9), 3.43(3H, s), 3.51(2H, s), 7.18-7.29(2H, m), 7.36-7.45(2H, m) I-272 0.96(3H, s), 1.05(3H, s), 1.25(3H, d, J=6.9), 1.26(3H, d, J=6.9), 2.61(1H, d, J=12), 2.70(1H, d, J=12), 3.39(1H, sept, J=6.9), 3.45-3.58(2H, m), 7.02-7.07(2H, m), 7.11-7.18(1H, m), 7.38-7.45(2H, m), 7.61-7.70(2H, m) I-273 0.84(3H, s), 1.00(3H, s), 1.25(3H, d, J=6.9), 1.29(3H, J=6.9), 2.43(3H, s), 2.53(1H, d, J=12), 2.64(1H, d, J=12), 3.29(1H, d, J=16), 3.42(1H, d, J=16), 3.47(1H, sept, J=6.9), 7.09-7.19(2H, m), 7.24-7.29(2H, m), 7.38-7.45(2H, m), 7.81-7.86(2H, m) I-274 0.99(6H, s), 1.19(6H, d, J=6.9), 2.40(3H, s), 2.67(2H, s), 2.87(1H, sept, J=6.9), 3.43(2H, s), 7.11-7.29(6H, m), 7.68(2H, d, J=8.1) I-275 1.07(6H, s), 1.26(6H, d, J=6.9), 1.38(3H, t, J=7.2), 2.71(2H, s), 2.93(1H, sept, J=6.9), 3.51(2H, s), 3.60(2H, q, J=7.2), 7.20-7.30(4H, m) I-276 1.19(6H, s), 1.23(6H, d, J=6.9), 2.77(2H, s), 2.87(1H, sept, J=6.9), 3.58(2H, s), 6.65-6.69(2H, m), 6.91(1H, d, J=7.5), 7.20(1H, t, J=7.5), 7.51(2H, d, J=9.3), 8.22(2H, d, J=9.3) I-277 0.99(6H, s), 1.20(6H, d, J=6.9), 2.67(2H, s), 2.88(1H, sept, J=6.9), 3.44(2H, s), 3.85(3H, s), 6.86-6.90(2H, m), 7.11-7.26(4H, m), 7.72-7.76(2H, m)

TABLE 40 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-278 1.03(6H, s), 1.20(6H, d, J=6.9), 2.70(2H, s), 2.88(1H, sept, J=6.9), 3.44(2H, s), 7.08-7.31(4H, m), 7.60(1H, t, J=8.4), 8.04(1H, d, J=8.4), 8.39(d, J=8.4), 8.74(1H, s) I-279 1.01(6H, s), 1.19(6H, d, J=6.9), 2.69(2H, s), 2.88(1H, sept, J=6.9), 3.42(2H, s), 7.09-7.32(4H, m), 7.68(2H, d, J=8.4), 7.92(2H, d, J=8.4), I-280 1.19(3H, s), 1.21(3H, s), 1.23-1.30(6H, m), 2.62(1H, d, J=12), 2.82(1H, sept, J=6.9), 3.02(1H, d, J=12), 3.46-3.70(2H, m), 6.53-6.60(2H, m), 6.86(1H, d, J=7.8), 7.13(1H, t, J=7.8), 7.28-7.40(2H, m), 7.61-7.66(1H, m), 7.90(1H, dd, J=7.5, 1.2)

The following compounds are within the scope of the present invention. These compounds can be prepared in accordance with the above examples. The numbers of left column in Table represent Compound No. TABLE 41

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ A-1  H Pr H H H CSSMe Me Me A-2  Pr^(i) H Cl H H CSSMe Me Me A-3  H Bu^(s) H H H CSSMe Me Me A-4  H H Bu^(s) H H CSSMe Me Me A-5  OPr H H H H CSSMe Me Me A-6  OBu H H H H CSSMe Me Me A-7  H SEt H H H CSSMe Me Me A-8  H H SEt H H CSSMe Me Me A-9  H SPr^(i) H H H CSSMe Me Me A-10 H H SPr^(i) H H CSSMe Me Me A-11 H OCHF₂ H H H CSSMe Me Me A-12 Pr^(i) H NMe₂ H H CSSMe Me Me A-13 Pr^(i) NMe₂ H H H CSSMe Me Me A-14 Et Et H H H CSSMe Me Me A-15 H Et Et H H CSSMe Me Me A-16 Bu^(i) H H H H CSSMe Me Me A-17 H Bu^(t) H H H CSSMe Me Me A-18 H H Bu^(t) H H CSSMe Me Me A-19 H N(Me)Et H H H CSSMe Me Me A-20 H N(Me)Pr H H H CSSMe Me Me A-21 NPr₂ H H H H CSSMe Me Me A-22 H NPr₂ H H H CSSMe Me Me A-23 H H NPr₂ H H CSSMe Me Me A-24 H NPr₂ Me H H CSSMe Me Me A-25 H Bu^(t) H H H CSSMe Me Me A-26 H CH₂OMe H H H CSSMe Me Me A-27 H H CH₂OMe H H CSSMe Me Me A-28 CH₂OEt H H H H CSSMe Me Me A-29 H CH₂OEt H H H CSSMe Me Me A-30 H H CH₂OEt H H CSSMe Me Me A-31 CH₂SMe H H H H CSSMe Me Me A-32 H CH₂SMe H H H CSSMe Me Me A-33 H H CH₂SMe H H CSSMe Me Me A-34 CH₂SEt H H H H CSSMe Me Me A-35 H CH₂SEt H H H CSSMe Me Me A-36 H H CH₂SEt H H CSSMe Me Me A-37 CH₂NMe₂ H H H H CSSMe Me Me A-38 H CH₂NMe₂ H H H CSSMe Me Me A-39 H H CH₂NMe₂ H H CSSMe Me Me A-40 CH₂NEt₂ H H H H CSSMe Me Me A-41 H CH₂NEt₂ H H H CSSMe Me Me A-42 H H CH₂NEt₂ H H CSSMe Me Me A-43 OCH₂CH₂Ome H H H H CSSMe Me Me A-44 H OCH₂CH₂OMe H H H CSSMe Me Me A-45 H H OCH₂CH₂OMe H H CSSMe Me Me A-46 OCH₂CH₂SMe H H H H CSSMe Me Me A-47 H OCH₂CH₂SMe H H H CSSMe Me Me A-48 H H OCH₂CH₂SMe H H CSSMe Me Me A-49 OCH₂CH₂NMe₂ H H H H CSSMe Me Me A-50 H OCH₂CH₂NMe₂ H H H CSSMe Me Me A-51 H H OCH₂CH₂NMe₂ H H CSSMe Me Me A-52 F H F H H CSSMe Me Me A-53 Cl H Cl H H CSSMe Me Me A-54 OMe Cl H H H CSSMe Me Me A-55 OMe H Cl H H CSSMe Me Me A-56 OMe Me H H H CSSMe Me Me A-57 OMe Et H H H CSSMe Me Me A-58 OMe H Et H H CSSMe Me Me A-59 OMe H Pr^(i) H H CSSMe Me Me A-60 OMe H OEt H H CSSMe Me Me A-61 OMe H OPr H H CSSMe Me Me A-62 OMe NMe₂ H H H CSSMe Me Me A-63 OMe NEt₂ H H H CSSMe Me Me A-64 OEt NMe₂ H H H CSSMe Me Me A-65 OEt NEt₂ H H H CSSMe Me Me A-66 H OMe F H H CSSMe Me Me A-67 H OMe Cl H H CSSMe Me Me A-68 H OMe OPr^(i) H H CSSMe Me Me A-69 H OEt OPr H H CSSMe Me Me A-70 H OEt OPr^(i) H H CSSMe Me Me A-71 H OEt OBu H H CSSMe Me Me A-72 SMe SMe H H H CSSMe Me Me A-73 SMe H SMe H H CSSMe Me Me A-74 NMe₂ NM_(e2) H H H OSSMe Me Me A-75 NMe₂ H NMe₂ H H CSSMe Me Me

TABLE 42

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ B-1  H H H H H COSMe Me Me B-2  Cl H H H H COSMe Me Me B-3  Br H H H H COSMe Me Me B-4  Me H H H H COSMe Me Me B-5  Et H H H H COSMe Me Me B-6  Bu H H H H COSMe Me Me B-7  Bu^(i) H H H H COSMe Me Me B-8  Bu^(i) H H H H COSMe Me Me B-9  OEt H H H H COSMe Me Me B-10 OPr H H H H COSMe Me Me B-11 OCHF₂ H H H H COSMe Me Me B-12 OCF₃ H H H H COSMe Me Me B-13 CF₃ H H H H COSMe Me Me B-14 SMe H H H H COSMe Me Me B-15 SEt H H H H COSMe Me Me B-16 SPr^(i) H H H H COSMe Me Me B-17 NMe₂ H H H H COSMe Me Me B-18 NEt₂ H H H H COSMe Me Me B-19 H Cl H H H COSMe Me Me B-20 H Br H H H COSMe Me Me B-21 H Me H H H COSMe Me Me B-22 H Et H H H COSMe Me Me B-23 H Pr H H H COSMe Me Me B-24 H Bu H H H COSMe Me Me B-25 H Bu^(i) H H H COSMe Me Me

TABLE 43

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ B-26 H Bu^(s) H H H COSMe Me Me B-27 H Bu^(t) H H H COSMe Me Me B-28 H OMe H H H COSMe Me Me B-29 H OEt H H H COSMe Me Me B-30 H OPr H H H COSMe Me Me B-31 H OCHF₂ H H H COSMe Me Me B-32 H OCF₃ H H H COSMe Me Me B-33 H CF₃ H H H COSMe Me Me B-34 H SMe H H H COSMe Me Me B-35 H SEt H H H COSMe Me Me B-36 H SPr^(i) H H H COSMe Me Me B-37 H NMe₂ H H H COSMe Me Me B-38 H NEt₂ H H H COSMe Me Me B-39 H H Cl H H COSMe Me Me B-40 H H Br H H COSMe Me Me B-41 H H Me H H COSMe Me Me B-42 H H Pr H H COSMe Me Me B-43 H H Bu H H COSMe Me Me B-44 H H Bu^(i) H H COSMe Me Me B-45 H H Bu^(s) H H COSMe Me Me B-46 H H Bu^(t) H H COSMe Me Me B-47 H H OMe H H COSMe Me Me B-48 H H OEt H H COSMe Me Me B-49 H H OPr H H COSMe Me Me B-50 H H OCHF₂ H H COSMe Me Me

TABLE 44

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ B-51 H H OCF₃ H H COSMe Me Me B-52 H H CF₃ H H COSMe Me Me B-53 H H SMe H H COSMe Me Me B-54 H H SEt H H COSMe Me Me B-55 H H SPr^(i) H H COSMe Me Me B-56 H H NMe₂ H H COSMe Me Me B-57 H H NEt₂ H H COSMe Me Me B-58 Me Me H H H COSMe Me Me B-59 H Me Me H H COSMe Me Me B-60 Et Et H H H COSMe Me Me B-61 H Et Et H H COSMe Me Me B-62 OMe Me H H H COSMe Me Me B-63 OMe H Me H H COSMe Me Me B-64 NMe₂ Me H H H COSMe Me Me B-65 H NMe₂ Me H H COSMe Me Me B-66 Me NMe₂ H H H COSMe Me Me B-67 NMe₂ Cl H H H COSMe Me Me B-68 Me NEt₂ H H H COSMe Me Me B-69 H NEt₂ Me H H COSMe Me Me B-70 Pr^(i) H F H H COSMe Me Me

TABLE 45

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ C-1  H H H H H CSSEt Me Me C-2  Cl H H H H CSSEt Me Me C-3  Br H H H H CSSEt Me Me C-4  Me H H H H CSSEt Me Me C-5  Et H H H H CSSEt Me Me C-6  Pr H H H H CSSEt Me Me C-7  Bu H H H H CSSEt Me Me C-8  Bu^(i) H H H H CSSEt Me Me C-9  Bu^(t) H H H H CSSEt Me Me C-10 OMe H H H H CSSEt Me Me C-11 OPr H H H H CSSEt Me Me C-12 OCHF₂ H H H H CSSEt Me Me C-13 OCF₃ H H H H CSSEt Me Me C-14 CF₃ H H H H CSSEt Me Me C-15 SEt H H H H CSSEt Me Me C-16 SPr^(i) H H H H CSSEt Me Me C-17 NEt₂ H H H H CSSEt Me Me C-18 H Cl H H H CSSEt Me Me C-19 H Br H H H CSSEt Me Me C-20 H Me H H H CSSEt Me Me C-21 H Et H H H CSSEt Me Me C-22 H Pr H H H CSSEt Me Me C-23 H Bu H H H CSSEt Me Me C-24 H Bu^(i) H H H CSSEt Me Me C-25 H Bu^(s) H H H CSSEt Me Me

TABLE 46

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ C-26 H Bu^(t) H H H CSSEt Me Me C-27 H OMe H H H CSSEt Me Me C-28 H OEt H H H CSSEt Me Me C-29 H OPr H H H CSSEt Me Me C-30 H OCHF₂ H H H CSSEt Me Me C-31 H OCF₃ H H H CSSEt Me Me C-32 H CF₃ H H H CSSEt Me Me C-33 H SMe H H H CSSEt Me Me C-34 H SEt H H H CSSEt Me Me C-35 H SPr^(i) H H H CSSEt Me Me C-36 H NEt₂ H H H CSSEt Me Me C-37 H H Cl H H CSSEt Me Me C-38 H H Br H H CSSEt Me Me C-39 H H Me H H CSSEt Me Me C-40 H H Et H H CSSEt Me Me C-41 H H Pr H H CSSEt Me Me C-42 H H Bu H H CSSEt Me Me C-43 H H Bu^(i) H H CSSEt Me Me C-44 H H Bu₃ H H CSSEt Me Me C-45 H H Bu H H CSSEt Me Me C-46 H H OMe H H CSSEt Me Me C-47 H H OEt H H CSSEt Me Me C-48 H H OPr H H CSSEt Me Me C-49 H H OCHF₂ H H CSSEt Me Me C-50 H H OCF₃ H H CSSEt Me Me

TABLE 47

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ C-51 H H CF₃ H H CSSEt Me Me C-52 H H SMe H H CSSEt Me Me C-53 H H SEt H H CSSEt Me Me C-54 H H SPr^(i) H H CSSEt Me Me C-55 H H NMe₂ H H CSSEt Me Me C-56 H H NEt₂ H H CSSEt Me Me C-57 Me Me H H H CSSEt Me Me C-58 H Me Me H H CSSEt Me Me C-59 Et Et H H H CSSEt Me Me C-60 H Et Et H H CSSEt Me Me C-61 OMe Me H H H CSSEt Me Me C-62 OMe H Me H H CSSEt Me Me C-63 NMe₂ Me H H H CSSEt Me Me C-64 H NMe₂ Me H H CSSEt Me Me C-65 Me NMe₂ H H H CSSEt Me Me C-66 NMe₂ CI H H H CSSEt Me Me C-67 Me NEt₂ H H H CSSEt Me Me C-68 H NEt₂ Me H H CSSEt Me Me C-69 Pr^(i) H F H H CSSEt Me Me C-70 OMe H OMe H H CSSEt Me Me C-71 H OMe OMe H H CSSEt Me Me C-72 H OMe OEt H H CSSEt Me Me C-73 H OEt OMe H H CSSEt Me Me C-74 H OEt OEt H H CSSEt Me Me C-75 OMe H Me H H CSSEt Me Me

TABLE 48

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ D-1  Br H H H H COSEt Me Me D-2  Bu^(i) H H H H COSEt Me Me D-3  OPr H H H H COSEt Me Me D-4  OCHF₂ H H H H COSEt Me Me D-5  OCF₃ H H H H COSEt Me Me D-6  NEt₂ H H H H COSEt Me Me D-7  H Cl H H H COSEt Me Me D-8  H Br H H H COSEt Me Me D-9  H Et H H H COSEt Me Me D-10 H Pr H H H COSEt Me Me D-11 H Bu H H H COSEt Me Me D-12 H Bu^(i) H H H COSEt Me Me D-13 H Bu^(s) H H H COSEt Me Me D-14 H Bu^(t) H H H COSEt Me Me D-15 H OEt H H H COSEt Me Me D-16 H OPr H H H COSEt Me Me D-17 H OCHF₂ H H H COSEt Me Me D-18 H OCF₃ H H H COSEt Me Me D-19 H CF₃ H H H COSEt Me Me D-20 H SMe H H H COSEt Me Me D-21 H SEt H H H COSEt Me Me D-22 H SPr^(i) H H H COSEt Me Me D-23 H NMe₂ H H H COSEt Me Me D-24 H NEt2 H H H COSEt Me Me D-25 H H Br H H COSEt Me Me

TABLE 49

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ D-26 H H Et H H COSEt Me Me D-27 H H Pr H H COSEt Me Me D-28 H H Bu H H COSEt Me Me D-29 H H Bu^(i) H H COSEt Me Me D-30 H H Bu^(s) H H COSEt Me Me D-31 H H Bu^(t) H H COSEt Me Me D-32 H H OMe H H COSEt Me Me D-33 H H OEt H H COSEt Me Me D-34 H H OPr H H COSEt Me Me D-35 H H OCHF₂ H H COSEt Me Me D-36 H H OCF₃ H H COSEt Me Me D-37 H H CF₃ H H COSEt Me Me D-38 H H SMe H H COSEt Me Me D-39 H H SEt H H COSEt Me Me D-40 H H SPr^(i) H H COSEt Me Me D-41 H H NMe₂ H H COSEt Me Me D-42 H H NEt₂ H H COSEt Me Me D-43 Et Et H H H COSEt Me Me D-44 H Et Et H H COSEt Me Me D-45 OMe Me H H H COSEt Me Me D-46 OMe H Me H H COSEt Me Me D-47 NMe₂ Me H H H COSEt Me Me D-48 H NMe₂ Me H H COSEt Me Me D-49 H OEt OMe H H COSEt Me Me D-50 H OEt OEt H H COSEt Me Me

TABLE 50

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ E-1  H H H H H CSSMe Et Et E-2  Cl H H H H CSSMe Et Et E-3  Br H H H H CSSMe Et Et E-4  Me H H H H CSSMe Et Et E-5  Et H H H H CSSMe Et Et E-6  Pr H H H H CSSMe Et Et E-7  Bu H H H H CSSMe Et Et E-8  Bu^(i) H H H H CSSMe Et Et E-9 Bu^(t) H H H H CSSMe Et Et E-10 OMe H H H H CSSMe Et Et E-11 OEt H H H H CSSMe Et Et E-12 OPr^(i) H H H H CSSMe Et Et E-13 OPr H H H H CSSMe Et Et E-14 OCHF₂ H H H H CSSMe Et Et E-15 OCF₃ H H H H CSSMe Et Et E-16 CF₃ H H H H CSSMe Et Et E-17 SMe H H H H CSSMe Et Et E-18 SEt H H H H CSSMe Et Et E-19 SPr^(i) H H H H CSSMe Et Et E-20 NMe₂ H H H H CSSMe Et Et E-21 NEt₂ H H H H CSSMe Et Et E-22 H Cl H H H CSSMe Et Et E-23 H Br H H H CSSMe Et Et E-24 H Me H H H CSSMe Et Et E-25 H Et H H H CSSMe Et Et

TABLE 51

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ E-26 H Pr H H H CSSMe Et Et E-27 H Pr^(i) H H H CSSMe Et Et E-28 H Bu H H H CSSMe Et Et E-29 H Bu^(i) H H H CSSMe Et Et E-30 H Bu^(s) H H H CSSMe Et Et E-31 H Bu^(t) H H H CSSMe Et Et E-32 H OMe H H H CSSMe Et Et E-33 H OEt H H H CSSMe Et Et E-34 H OPr H H H CSSMe Et Et E-35 H OPr^(i) H H H CSSMe Et Et E-36 H OCHF₂ H H H CSSMe Et Et E-37 H OCF₃ H H H CSSMe Et Et E-38 H CF₃ H H H CSSMe Et Et E-39 H SMe H H H CSSMe Et Et E-40 H SEt H H H CSSMe Et Et E-41 H SPr^(i) H H H CSSMe Et Et E-42 H NMe₂ H H H CSSMe Et Et E-43 H NEt₂ H H H CSSMe Et Et E-44 H H Cl H H CSSMe Et Et E-45 H H Br H H CSSMe Et Et E-46 H H Me H H CSSMe Et Et E-47 H H Et H H CSSMe Et Et E-48 H H Pr H H CSSMe Et Et E-49 H H Pr^(i) H H CSSMe Et Et E-50 H H Bu H H CSSMe Et Et

TABLE 52

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ E-51 H H Bu^(i) H H CSSMe Et Et E-52 H H Bu^(s) H H CSSMe Et Et E-53 H H Bu^(t) H H CSSMe Et Et E-54 H H OMe H H CSSMe Et Et E-55 H H OEt H H CSSMe Et Et E-56 H H OPr H H CSSMe Et Et E-57 H H OPr^(i) H H CSSMe Et Et E-58 H H OCHF₂ H H CSSMe Et Et E-59 H H OCF₃ H H CSSMe Et Et E-60 H H CF₃ H H CSSMe Et Et E-61 H H SMe H H CSSMe Et Et E-62 H H SEt H H CSSMe Et Et E-63 H H SPr^(i) H H CSSMe Et Et E-64 H H NMe₂ H H CSSMe Et Et E-65 H H NEt₂ H H CSSMe Et Et E-66 Me NMe₂ H H H CSSMe Et Et E-67 NMe₂ Cl H H H CSSMe Et Et E-68 Me NEt₂ H H H CSSMe Et Et E-69 H NEt₂ Me H H CSSMe Et Et E-70 Pr^(i) H F H H CSSMe Et Et E-71 OMe H OMe H H CSSMe Et Et E-72 H OMe OMe H H CSSMe Et Et E-73 H OMe OEt H H CSSMe Et Et E-74 H OEt OMe H H CSSMe Et Et E-75 H OEt OEt H H CSSMe Et Et

TABLE 53

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ F-1  H H H H H CSSMe Pr Pr F-2  Cl H H H H CSSMe Pr Pr F-3  Br H H H H CSSMe Pr Pr F-4  Me H H H H CSSMe Pr Pr F-S  Et H H H H CSSMe Pr Pr F-6  Pr H H H H CSSMe Pr Pr F-7  Bu H H H H CSSMe Pr Pr F-8  Bu^(i) H H H H CSSMe Pr Pr F-9  Bu^(t) H H H H CSSMe Pr Pr F-10 OMe H H H H CSSMe Pr Pr F-11 OEt H H H H CSSMe Pr Pr F-12 OPr^(i) H H H H CSSMe Pr Pr F-13 OPr H H H H CSSMe Pr Pr F-14 OCHF₂ H H H H CSSMe Pr Pr F-15 OCF₃ H H H H CSSMe Pr Pr F-16 CF₃ H H H H CSSMe Pr Pr F-17 SMe H H H H CSSMe Pr Pr F-18 SEt H H H H CSSMe Pr Pr F-19 SPr^(i) H H H H CSSMe Pr Pr F-20 NMe₂ H H H H CSSMe Pr Pr F-21 NEt₂ H H H H CSSMe Pr Pr F-22 H Cl H H H CSSMe Pr Pr F-23 H Br H H H CSSMe Pr Pr F-24 H Me H H H CSSMe Pr Pr F-25 H Et H H H CSSMe Pr Pr

TABLE 54

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ F-26 H Pr H H H CSSMe Pr Pr F-27 H Pr^(i) H H H CSSMe Pr Pr F-28 H Bu H H H CSSMe Pr Pr F-29 H Bu^(i) H H H CSSMe Pr Pr F-30 H Bu^(s) H H H CSSMe Pr Pr F-31 H Bu^(t) H H H CSSMe Pr Pr F-32 H OMe H H H CSSMe Pr Pr F-33 H OEt H H H CSSMe Pr Pr F-34 H OPr H H H CSSMe Pr Pr F-35 H OPr^(i) H H H CSSMe Pr Pr F-36 H OCHF₂ H H H CSSMe Pr Pr F-37 H OCF₃ H H H CSSMe Pr Pr F-38 H CF₃ H H H CSSMe Pr Pr F-39 H SMe H H H CSSMe Pr Pr F-40 H SEt H H H CSSMe Pr Pr F-41 H SPr^(i) H H H CSSMe Pr Pr F-42 H NMe₂ H H H CSSMe Pr Pr F-43 H NEt₂ H H H CSSMe Pr Pr F-44 H H Cl H H CSSMe Pr Pr F-45 H H Br H H CSSMe Pr Pr F-46 H H Me H H CSSMe Pr Pr F-47 H H Et H H CSSMe Pr Pr F-48 H H Pr H H CSSMe Pr Pr F-49 H H Pr^(i) H H CSSMe Pr Pr F-50 H H Bu H H CSSMe Pr Pr

TABLE 55

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ F-51 H H Bu^(i) H H CSSMe Pr Pr F-52 H H Bu^(s) H H CSSMe Pr Pr F-53 H H Bu^(t) H H CSSMe Pr Pr F-54 H H OMe H H CSSMe Pr Pr F-55 H H QEt H H CSSMe Pr Pr F-56 H H OPr H H CSSMe Pr Pr F-57 H H OPr^(i) H H CSSMe Pr Pr F-58 H H OCHF₂ H H CSSMe Pr Pr F-59 H H OCF₃ H H CSSMe Pr Pr F-60 H H CF₃ H H CSSMe Pr Pr F-61 H H SMe H H CSSMe Pr Pr F-62 H H SEt H H CSSMe Pr Pr F-63 H H SPr^(i) H H CSSMe Pr Pr F-64 H H NMe₂ H H CSSMe Pr Pr F-65 H H NEt₂ H H CSSMe Pr Pr F-66 Me NMe₂ H H H CSSMe Pr Pr F-67 NMe₂ Cl H H H CSSMe Pr Pr F-68 Me NEt₂ H H H CSSMe Pr Pr F-69 H NEt₂ Me H H CSSMe Pr Pr F-70 Bu^(s) H H H H CSSMe Pr Pr F-71 OMe H OMe H H CSSMe Pr Pr F-72 H OMe OMe H H CSSMe Pr Pr F-73 H OMe OEt H H CSSMe Pr Pr F-74 H OEt OMe H H CSSMe Pr Pr F-75 H OEt OEt H H CSSMe Pr Pr

TABLE 56

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ G-1  H H H H H CSSEt Et Et G-2  Cl H H H H CSSEt Et Et G-3  Br H H H H CSSEt Et Et G-4  Me H H H H CSSEt Et Et G-5  Et H H H H CSSEt Et Et G-6  Pr H H H H CSSEt Et Et G-7  Bu H H H H CSSEt Et Et G-8  Bu^(i) H H H H CSSEt Et Et G-9  Bu^(t) H H H H CSSEt Et Et G-10 OMe H H H H CSSEt Et Et G-11 OEt H H H H CSSEt Et Et G-12 OPr^(i) H H H H CSSEt Et Et G-13 OPr H H H H CSSEt Et Et G-14 OCHF₂ H H H H CSSEt Et Et G-15 OCF₃ H H H H CSSEt Et Et G-16 CF₃ H H H H CSSEt Et Et G-17 SMe H H H H CSSEt Et Et G-18 SEt H H H H CSSEt Et Et G-19 SPr^(i) H H H H CSSEt Et Et G-20 NMe₂ H H H H CSSEt Et Et G-21 NEt₂ H H H H CSSEt Et Et G-22 H Cl H H H CSSEt Et Et G-23 H Br H H H CSSEt Et Et G-24 H Me H H H CSSEt Et Et G-25 H Et H H H CSSEt Et Et

TABLE 57

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ G-26 H Pr H H H CSSEt Et Et G-27 H Pr^(i) H H H CSSEt Et Et G-28 H Bu H H H CSSEt Et Et G-29 H Bu^(i) H H H CSSEt Et Et G-30 H Bu^(s) H H H CSSEt Et Et G-31 H Bu^(t) H H H CSSEt Et Et G-32 H OMe H H H CSSEt Et Et G-33 H OEt H H H CSSEt Et Et G-34 H OPr H H H CSSEt Et Et G-35 H OPr^(i) H H H CSSEt Et Et G-36 H OCHF₂ H H H CSSEt Et Et G-37 H OCF₃ H H H CSSEt Et Et G-38 H CF₃ H H H CSSEt Et Et G-39 H SMe H H H CSSEt Et Et G-40 H SEt H H H CSSEt Et Et G-41 H SPr^(i) H H H CSSEt Et Et G-42 H NMe₂ H H H CSSEt Et Et G-43 H NEt₂ H H H CSSEt Et Et G-44 H H Cl H H CSSEt Et Et G-45 H H Br H H CSSEt Et Et G-46 H H Me H H CSSEt Et Et G-47 H H Et H H CSSEt Et Et G-48 H H Pr H H CSSEt Et Et G-49 H H Pr^(i) H H CSSEt Et Et G-50 H H Bu H H CSSEt Et Et

TABLE 58

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ G-51 H H Bu^(i) H H CSSEt Et Et G-52 H H Bu^(s) H H CSSEt Et Et G-53 H H Bu^(t) H H CSSEt Et Et G-54 H H OMe H H CSSEt Et Et G-55 H H OEt H H CSSEt Et Et G-56 H H OPr H H CSSEt Et Et G-57 H H OPr^(i) H H CSSEt Et Et G-58 H H OCHF₂ H H CSSEt Et Et G-59 H H OCF₃ H H CSSEt Et Et G-60 H H CF₃ H H CSSEt Et Et G-61 H H SMe H H CSSEt Et Et G-62 H H SEt H H CSSEt Et Et G-63 H H SPr^(i) H H CSSEt Et Et G-64 H H NMe₂ H H CSSEt Et Et G-65 H H NEt₂ H H CSSEt Et Et G-66 Me NMe₂ H H H CSSEt Et Et G-67 NMe₂ Cl H H H CSSEt Et Et G-68 Me NEt₂ H H H CSSEt Et Et G-69 H NEt₂ Me H H CSSEt Et Et G-70 Bu^(s) H H H H CSSEt Et Et G-71 OMe H OMe H H CSSEt Et Et G-72 H OMe OMe H H CSSEt Et Et G-73 H OMe OEt H H CSSEt Et Et G-74 H OEt OMe H H CSSEt Et Et G-75 H OEt OEt H H CSSEt Et Et

TABLE 59

R1 R2 R3 R4 R5 R6 R7 R8 H-1  H H H H H CSSMe —(CH₂)₂— H-2  Cl H H H H CSSMe —(CH₂)₂— H-3  Br H H H H CSSMe —(CH₂)₂— H-4  Me H H H H CSSMe —(CH₂)₂— H-5  Et H H H H CSSMe —(CH₂)₂— H-6  Pr H H H H CSSMe —(CH₂)₂— H-7  Bu H H H H CSSMe —(CH₂)₂— H-8  Bu^(i) H H H H CSSMe —(CH₂)₂— H-9  Bu^(t) H H H H CSSMe —(CH₂)₂— H-10 OMe H H H H CSSMe —(CH₂)₂— H-11 OEt H H H H CSSMe —(CH₂)₂— H-12 OPr^(i) H H H H CSSMe —(CH₂)₂— H-13 OPr H H H H CSSMe —(CH₂)₂— H-14 OCHF₂ H H H H CSSMe —(CH₂)₂— H-15 OCF₃ H H H H CSSMe —(CH₂)₂— H-16 CF₃ H H H H CSSMe —(CH₂)₂— H-17 SMe H H H H CSSMe —(CH₂)₂— H-18 SEt H H H H CSSMe —(CH₂)₂— H-19 SPr^(i) H H H H CSSMe —(CH₂)₂— H-20 NMe₂ H H H H CSSMe —(CH₂)₂— H-21 NEt₂ H H H H CSSMe —(CH₂)₂— H-22 H Cl H H H CSSMe —(CH₂)₂— H-23 H Br H H H CSSMe —(CH₂)₂— H-24 H Me H H H CSSMe —(CH₂)₂— H-25 H Et H H H CSSMe —(CH₂)₂—

TABLE 60

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ H-26 H Pr H H H CSSMe —(CH₂)₂— H-27 H Pr^(i) H H H CSSMe —(CH₂)₂— H-28 H Bu H H H CSSMe —(CH₂)₂— H-29 H Bu^(i) H H H CSSMe —(CH₂)₂— H-30 H Bu^(s) H H H CSSMe —(CH₂)₂— H-31 H Bu^(t) H H H CSSMe —(CH₂)₂— H-32 H OMe H H H CSSMe —(CH₂)₂— H-33 H OEt H H H CSSMe —(CH₂)₂— H-34 H OPr H H H CSSMe —(CH₂)₂— H-35 H OPr^(i) H H H CSSMe —(CH₂)₂— H-36 H OCHF₂ H H H CSSMe —(CH₂)₂— H-37 H OCF₃ H H H CSSMe —(CH₂)₂— H-38 H CF₃ H H H CSSMe —(CH₂)₂— H-39 H SMe H H H CSSMe —(CH₂)₂— H-40 H SEt H H H CSSMe —(CH₂)₂— H-41 H SPr^(i) H H H CSSMe —(CH₂)₂— H-42 H NMe₂ H H H CSSMe —(CH₂)₂— H-43 H NEt₂ H H H CSSMe —(CH₂)₂— H-44 H H Cl H H CSSMe —(CH₂)₂— H-45 H H Br H H CSSMe —(CH₂)₂— H-46 H H Me H H CSSMe —(CH₂)₂— H-47 H H Et H H CSSMe —(CH₂)₂— H-48 H H Pr H H CSSMe —(CH₂)₂— H-49 H H Pr^(i) H H CSSMe —(CH₂)₂— H-50 H H Bu H H CSSMe —(CH₂)₂—

TABLE 61

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ H-51 H H Bu^(i) H H CSSMe —(CH₂)₂— H-52 H H Bu^(s) H H CSSMe —(CH₂)₂— H-53 H H Bu^(t) H H CSSMe —(CH₂)₂— H-54 H H OMe H H CSSMe —(CH₂)₂— H-55 H H OEt H H CSSMe —(CH₂)₂— H-56 H H OPr H H CSSMe —(CH₂)₂— H-57 H H OPr^(i) H H CSSMe —(CH₂)₂— H-58 H H OCHF₂ H H CSSMe —(CH₂)₂— H-59 H H OCF₃ H H CSSMe —(CH₂)₂— H-60 H H CF₃ H H CSSMe —(CH₂)₂— H-61 H H SMe H H CSSMe —(CH₂)₂— H-62 H H SEt H H CSSMe —(CH₂)₂— H-63 H H SPr^(i) H H CSSMe —(CH₂)₂— H-64 H H NMe₂ H H CSSMe —(CH₂)₂— H-65 H H NEt₂ H H CSSMe —(CH₂)₂— H-66 Me NMe₂ H H H CSSMe —(CH₂)₂— H-67 NMe₂ Cl H H H CSSMe —(CH₂)₂— H-68 Me NEt₂ H H H CSSMe —(CH₂)₂— H-69 H NEt₂ Me H H CSSMe —(CH₂)₂— H-70 Bu^(s) H H H H CSSMe —(CH₂)₂— H-71 OMe H OMe H H CSSMe —(CH₂)₂— H-72 H OMe OMe H H CSSMe —(CH₂)₂— H-73 H OMe OEt H H CSSMe —(CH₂)₂— H-74 H OEt OMe H H CSSMe —(CH₂)₂— H-75 H OEt OEt H H CSSMe —(CH₂)₂—

TABLE 62

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ N-1  H H H H H CSSMe —(CH₂)₄— N-2  Cl H H H H CSSMe —(CH₂)₄— N-3  Br H H H H CSSMe —(CH₂)₄— N-4  Me H H H H CSSMe —(CH₂)₄— N-5  Et H H H H CSSMe —(CH₂)₄— N-6  Pr H H H H CSSMe —(CH₂)₄— N-7  Bu H H H H CSSMe —(CH₂)₄— N-8  Bu^(i) H H H H CSSMe —(CH₂)₄— N-9  Bu^(t) H H H H CSSMe —(CH₂)₄— N-10 OMe H H H H CSSMe —(CH₂)₄— N-11 OEt H H H H CSSMe —(CH₂)₄— N-12 OPr^(i) H H H H CSSMe —(CH₂)₄— N-13 OPr H H H H CSSMe —(CH₂)₄— N-14 OCHF₂ H H H H CSSMe —(CH₂)₄— N-15 OCF₃ H H H H CSSMe —(CH₂)₄— N-16 CF₃ H H H H CSSMe —(CH₂)₄— N-17 SMe H H H H CSSMe —(CH₂)₄— N-18 SEt H H H H CSSMe —(CH₂)₄— N-19 SPr^(i) H H H H CSSMe —(CH₂)₄— N-20 NMe₂ H H H H CSSMe —(CH₂)₄— N-21 NEt₂ H H H H CSSMe —(CH₂)₄— N-22 H Cl H H H CSSMe —(CH₂)₄— N-23 H Br H H H CSSMe —(CH₂)₄— N-24 H Me H H H CSSMe —(CH₂)₄— N-25 H Et H H H CSSMe —(CH₂)₄—

TABLE 63

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ N-26 H Pr H H H CSSMe —(CH₂)₄— N-27 H Pr^(i) H H H CSSMe —(CH₂)₄— N-28 H Bu H H H CSSMe —(CH₂)₄— N-29 H Bu^(i) H H H CSSMe —(CH₂)₄— N-30 H Bu^(s) H H H CSSMe —(CH₂)₄— N-31 H Bu^(t) H H H CSSMe —(CH₂)₄— N-32 H OMe H H H CSSMe —(CH₂)₄— N-33 H OEt H H H CSSMe —(CH₂)₄— N-34 H OPr H H H CSSMe —(CH₂)₄— N-35 H OPr^(i) H H H CSSMe —(CH₂)₄— N-36 H OCHF₂ H H H CSSMe —(CH₂)₄— N-37 H OCF₃ H H H CSSMe —(CH₂)₄— N-38 H CF₃ H H H CSSMe —(CH₂)₄— N-39 H SMe H H H CSSMe —(CH₂)₄— N-40 H SEt H H H CSSMe —(CH₂)₄— N-41 H SPr^(i) H H H CSSMe —(CH₂)₄— N-42 H NMe₂ H H H CSSMe —(CH₂)₄— N-43 H NEt₂ H H H CSSMe —(CH₂)₄— N-44 H H Cl H H CSSMe —(CH₂)₄— N-45 H H Br H H CSSMe —(CH₂)₄— N-46 H H Me H H CSSMe —(CH₂)₄— N-47 H H Et H H CSSMe —(CH₂)₄— N-48 H H Pr H H CSSMe —(CH₂)₄— N-49 H H Pr^(i) H H CSSMe —(CH₂)₄— N-50 H H Bu H H CSSMe —(CH₂)₄—

TABLE 64

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ N-51 H H Bu^(i) H H CSSMe —(CH₂)₄— N-52 H H Bu^(s) H H CSSMe —(CH₂)₄— N-53 H H Bu^(t) H H CSSMe —(CH₂)₄— N-54 H H OMe H H CSSMe —(CH₂)₄— N-55 H H OEt H H CSSMe —(CH₂)₄— N-56 H H OPr H H CSSMe —(CH₂)₄— N-57 H H OPr^(i) H H CSSMe —(CH₂)₄— N-58 H H OCHF₂ H H CSSMe —(CH₂)₄— N-59 H H OCF₃ H H CSSMe —(CH₂)₄— N-60 H H CF₃ H H CSSMe —(CH₂)₄— N-61 H H SMe H H CSSMe —(CH₂)₄— N-62 H H SEt H H CSSMe —(CH₂)₄— N-63 H H SPr^(i) H H CSSMe —(CH₂)₄— N-64 H H NMe₂ H H CSSMe —(CH₂)₄— N-65 H H NEt₂ H H CSSMe —(CH₂)₄— N-66 Me NMe₂ H H H CSSMe —(CH₂)₄— N-67 NMe₂ Cl H H H CSSMe —(CH₂)₄— N-68 Me NEt₂ H H H CSSMe —(CH₂)₄— N-69 H NEt₂ Me H H CSSMe —(CH₂)₄— N-70 Bu^(s) H H H H CSSMe —(CH₂)₄— N-71 OMe H OMe H H CSSMe —(CH₂)₄— N-72 H OMe OMe H H CSSMe —(CH₂)₄— N-73 H OMe OEt H H CSSMe —(CH₂)₄— N-74 H OEt OMe H H CSSMe —(CH₂)₄— N-75 H OEt OEt H H CSSMe —(CH₂)₄—

TABLE 65

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ J-1  H H H H H CSSMe —(CH₂)₅— J-2  Cl H H H H CSSMe —(CH₂)₅— J-3  Br H H H H CSSMe —(CH₂)₅— J-4  Me H H H H CSSMe —(CH₂)₅— J-5  Et H H H H CSSMe —(CH₂)₅— J-6  Pr H H H H CSSMe —(CH₂)₅— J-7  Bu H H H H CSSMe —(CH₂)₅— J-8  Bu^(i) H H H H CSSMe —(CH₂)₅— J-9  Bu^(t) H H H H CSSMe —(CH₂)₅— J-10 OMe H H H H CSSMe —(CH₂)₅— J-11 OEt H H H H CSSMe —(CH₂)₅— J-12 OPr^(i) H H H H CSSMe —(CH₂)₅— J-13 OPr H H H H CSSMe —(CH₂)₅— J-14 OCHF₂ H H H H CSSMe —(CH₂)₅— J-15 OCF₃ H H H H CSSMe —(CH₂)₅— J-16 CF₃ H H H H CSSMe —(CH₂)₅— J-17 SMe H H H H CSSMe —(CH₂)₅— J-18 SEt H H H H CSSMe —(CH₂)₅— J-19 SPr^(i) H H H H CSSMe —(CH₂)₅— J-20 NMe₂ H H H H CSSMe —(CH₂)₅— J-21 NEt₂ H H H H CSSMe —(CH₂)₅— J-22 H Cl H H H CSSMe —(CH₂)₅— J-23 H Br H H H CSSMe —(CH₂)₅— J-24 H Me H H H CSSMe —(CH₂)₅— J-25 H Et H H H CSSMe —(CH₂)₅—

TABLE 66

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ J-26 H Pr H H H CSSMe —(CH₂)₅— J-27 H Pr^(i) H H H CSSMe —(CH₂)₅— J-28 H Bu H H H CSSMe —(CH₂)₅— J-29 H Bu^(i) H H H CSSMe —(CH₂)₅— J-30 H Bu^(s) H H H CSSMe —(CH₂)₅— J-31 H Bu^(t) H H H CSSMe —(CH₂)₅— J-32 H OMe H H H CSSMe —(CH₂)₅— J-33 H OEt H H H CSSMe —(CH₂)₅— J-34 H OPr H H H CSSMe —(CH₂)₅— J-35 H OPr^(i) H H H CSSMe —(CH₂)₅— J-36 H OCHF₂ H H H CSSMe —(CH₂)₅— J-37 H OCF₃ H H H CSSMe —(CH₂)₅— J-38 H CF₃ H H H CSSMe —(CH₂)₅— J-39 H SMe H H H CSSMe —(CH₂)₅— J-40 H SEt H H H CSSMe —(CH₂)₅— J-41 H SPr^(i) H H H CSSMe —(CH₂)₅— J-42 H NMe₂ H H H CSSMe —(CH₂)₅— J-43 H NEt₂ H H H CSSMe —(CH₂)₅— J-44 H H Cl H H CSSMe —(CH₂)₅— J-45 H H Br H H CSSMe —(CH₂)₅— J-46 H H Me H H CSSMe —(CH₂)₅— J-47 H H Et H H CSSMe —(CH₂)₅— J-48 H H Pr H H CSSMe —(CH₂)₅— J-49 H H Pr^(i) H H CSSMe —(CH₂)₅— J-50 H H Bu H H CSSMe —(CH₂)₅—

TABLE 67

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ J-51 H H Bu^(i) H H CSSMe —(CH₂)₅)— J-52 H H Bu^(s) H H CSSMe —(CH₂)₅)— J-53 H H Bu^(t) H H CSSMe —(CH₂)₅)— J-54 H H OMe H H CSSMe —(CH₂)₅)— J-55 H H OEt H H CSSMe —(CH₂)₅)— J-56 H H OPr H H CSSMe —(CH₂)₅)— J-57 H H OPr^(i) H H CSSMe —(CH₂)₅)— J-58 H H OCHF₂ H H CSSMe —(CH₂)₅)— J-59 H H OCF₃ H H CSSMe —(CH₂)₅)— J-60 H H CF₃ H H CSSMe —(CH₂)₅)— J-61 H H SMe H H CSSMe —(CH₂)₅)— J-62 H H SEt H H CSSMe —(CH₂)₅)— J-63 H H SPr^(i) H H CSSMe —(CH₂)₅)— J-64 H H NMe₂ H H CSSMe —(CH₂)₅)— J-65 H H NEt₂ H H CSSMe —(CH₂)₅)— J-66 Me NMe₂ H H H CSSMe —(CH₂)₅)— J-67 NMe₂ Cl H H H CSSMe —(CH₂)₅)— J-68 Me NEt₂ H H H CSSMe —(CH₂)₅)— J-69 H NEt₂ Me H H CSSMe —(CH₂)₅)— J-70 Bu^(s) H H H H CSSMe —(CH₂)₅)— J-71 OMe H OMe H H CSSMe —(CH₂)₅)— J-72 H OMe OMe H H CSSMe —(CH₂)₅)— J-73 H OMe OEt H H CSSMe —(CH₂)₅)— J-74 H OEt OMe H H CSSMe —(CH₂)₅)— J-75 H OEt OEt H H CSSMe —(CH₂)₅)—

TABLE 68

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ K-1  H H H H H COSEt Et Et K-2  Cl H H H H COSEt Et Et K-3  Br H H H H COSEt Et Et K-4  Me H H H H COSEt Et Et K-5  Et H H H H COSEt Et Et K-6  Pr H H H H COSEt Et Et K-7  Bu H H H H COSEt Et Et K-8  Bu^(i) H H H H COSEt Et Et K-9  Bu^(t) H H H H COSEt Et Et K-10 OMe H H H H COSEt Et Et K-11 OEt H H H H COSEt Et Et K-12 OPr^(i) H H H H COSEt Et Et K-13 OPr H H H H COSEt Et Et K-14 OCHF₂ H H H H COSEt Et Et K-15 OCF₃ H H H H COSEt Et Et K-16 CF₃ H H H H COSEt Et Et K-17 SMe H H H H COSEt Et Et K-18 SEt H H H H COSEt Et Et K-19 SPr^(i) H H H H COSEt Et Et K-20 NMe₂ H H H H COSEt Et Et K-21 NEt₂ H H H H COSEt Et Et K-22 H Cl H H H COSEt Et Et K-23 H Br H H H COSEt Et Et K-24 H Me H H H COSEt Et Et K-25 H Et H H H COSEt Et Et

TABLE 69

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ K-26 H Pr H H H COSEt Et Et K-27 H Pr^(i) H H H COSEt Et Et K-28 H Bu H H H COSEt Et Et K-29 H Bu^(i) H H H COSEt Et Et K-30 H Bu^(s) H H H COSEt Et Et K-31 H Bu^(t) H H H COSEt Et Et K-32 H OMe H H H COSEt Et Et K-33 H OEt H H H COSEt Et Et K-34 H OPr H H H COSEt Et Et K-35 H OPr^(i) H H H COSEt Et Et K-36 H OCHF₂ H H H COSEt Et Et K-37 H OCF₃ H H H COSEt Et Et K-38 H CF₃ H H H COSEt Et Et K-39 H SMe H H H COSEt Et Et K-40 H SEt H H H COSEt Et Et K-41 H SPr^(i) H H H COSEt Et Et K-42 H NMe₂ H H H COSEt Et Et K-43 H NEt₂ H H H COSEt Et Et K-44 H H Cl H H COSEt Et Et K-45 H H Br H H COSEt Et Et K-46 H H Me H H COSEt Et Et K-47 H H Et H H COSEt Et Et K-48 H H Pr H H COSEt Et Et K-49 H H Pr^(i) H H COSEt Et Et K-50 H H Bu H H COSEt Et Et

TABLE 70

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ K-51 H H Bu^(i) H H COSEt Et Et K-52 H H Bu^(s) H H COSEt Et Et K-53 H H Bu^(t) H H COSEt Et Et K-54 H H OMe H H COSEt Et Et K-55 H H OEt H H COSEt Et Et K-56 H H OPr H H COSEt Et Et K-57 H H OPr^(i) H H COSEt Et Et K-58 H H OCHF₂ H H COSEt Et Et K-59 H H OCF₃ H H COSEt Et Et K-60 H H CF₃ H H COSEt Et Et K-61 H H SMe H H COSEt Et Et K-62 H H SEt H H COSEt Et Et K-63 H H SPr^(i) H H COSEt Et Et K-64 H H NMe₂ H H COSEt Et Et K-65 H H NEt₂ H H COSEt Et Et K-66 Me NMe₂ H H H COSEt Et Et K-67 NMe₂ Cl H H H COSEt Et Et K-68 Me NEt₂ H H H COSEt Et Et K-69 H NEt₂ Me H H COSEt Et Et K-70 Bu^(s) H H H H COSEt Et Et K-71 OMe H OMe H H COSEt Et Et K-72 H OMe OMe H H COSEt Et Et K-73 H OMe OEt H H COSEt Et Et K-74 H OEt OMe H H COSEt Et Et K-75 H OEt OEt H H COSEt Et Et

TABLE 71

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ L-1  H H H H H COSMe Et Et L-2  Cl H H H H COSMe Et Et L-3  Br H H H H COSMe Et Et L-4  Me H H H H COSMe Et Et L-5  Et H H H H COSMe Et Et L-6  Pr H H H H COSMe Et Et L-7  Bu H H H H COSMe Et Et L-8  Bu^(i) H H H H COSMe Et Et L-9  Bu^(t) H H H H COSMe Et Et L-10 OMe H H H H COSMe Et Et L-11 OEt H H H H COSMe Et Et L-12 OPr^(i) H H H H COSMe Et Et L-13 OPr H H H H COSMe Et Et L-14 OCHF₂ H H H H COSMe Et Et L-15 OCF₃ H H H H COSMe Et Et L-16 CF₃ H H H H COSMe Et Et L-17 SMe H H H H COSMe Et Et L-18 SEt H H H H COSMe Et Et L-19 SPr^(i) H H H H COSMe Et Et L-20 NMe₂ H H H H COSMe Et Et L-21 NEt₂ H H H H COSMe Et Et L-22 H Cl H H H COSMe Et Et L-23 H Br H H H COSMe Et Et L-24 H Me H H H COSMe Et Et L-25 H Et H H H COSMe Et Et

TABLE 72

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ L-26 H Pr H H H COSMe Et Et L-27 H Pr^(i) H H H COSMe Et Et L-28 H Bu H H H COSMe Et Et L-29 H Bu^(i) H H H COSMe Et Et L-30 H Bu^(s) H H H COSMe Et Et L-31 H Bu^(t) H H H COSMe Et Et L-32 H OMe H H H COSMe Et Et L-33 H OEt H H H COSMe Et Et L-34 H OPr H H H COSMe Et Et L-35 H OPr^(i) H H H COSMe Et Et L-36 H OCHF₂ H H H COSMe Et Et L-37 H OCF₃ H H H COSMe Et Et L-38 H CF₃ H H H COSMe Et Et L-39 H SMe H H H COSMe Et Et L-40 H SEt H H H COSMe Et Et L-41 H SPr^(i) H H H COSMe Et Et L-42 H NMe₂ H H H COSMe Et Et L-43 H NEt₂ H H H COSMe Et Et L-44 H H Cl H H COSMe Et Et L-45 H H Br H H COSMe Et Et L-46 H H Me H H COSMe Et Et L-47 H H Et H H COSMe Et Et L-48 H H Pr H H COSMe Et Et L-49 H H Pr^(i) H H COSMe Et Et L-50 H H Bu H H COSMe Et Et

TABLE 73

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ L-51 H H Bu^(i) H H COSMe Et Et L-52 H H Bu^(s) H H COSMe Et Et L-53 H H Bu^(t) H H COSMe Et Et L-54 H H OMe H H COSMe Et Et L-55 H H OEt H H COSMe Et Et L-56 H H OPr H H COSMe Et Et L-57 H H OPr^(i) H H COSMe Et Et L-58 H H OCHF₂ H H COSMe Et Et L-59 H H OCF₃ H H COSMe Et Et L-60 H H CF₃ H H COSMe Et Et L-61 H H SMe H H COSMe Et Et L-62 H H SEt H H COSMe Et Et L-63 H H SPr^(i) H H COSMe Et Et L-64 H H NMe₂ H H COSMe Et Et L-65 H H NEt₂ H H COSMe Et Et L-66 Me NMe₂ H H H COSMe Et Et L-67 NMe₂ Cl H H H COSMe Et Et L-68 Me NEt₂ H H H COSMe Et Et L-69 H NEt₂ Me H H COSMe Et Et L-70 Bu^(s) H H H H COSMe Et Et L-71 Pr^(i) H H H H COSMe Et Et L-72 H OMe OMe H H COSMe Et Et L-73 H OMe OEt H H COSMe Et Et L-74 H OEt OMe H H COSMe Et Et L-75 H OEt OEt H H COSMe Et Et

TABLE 74

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ M-1  H H H H H COSMe —(CH₂)₄— M-2  Cl H H H H COSMe —(CH₂)₄— M-3  Br H H H H COSMe —(CH₂)₄— M-4  Me H H H H COSMe —(CH₂)₄— M-5  Et H H H H COSMe —(CH₂)₄— M-6  Pr H H H H COSMe —(CH₂)₄— M-7  Bu H H H H COSMe —(CH₂)₄— M-8  Bu^(i) H H H H COSMe —(CH₂)₄— M-9  Bu^(t) H H H H COSMe —(CH₂)₄— M-10 OMe H H H H COSMe —(CH₂)₄— M-11 OEt H H H H COSMe —(CH₂)₄— M-12 OPr^(i) H H H H COSMe —(CH₂)₄— M-13 OPr H H H H COSMe —(CH₂)₄— M-14 OCHF₂ H H H H COSMe —(CH₂)₄— M-15 OCF₃ H H H H COSMe —(CH₂)₄— M-16 CF₃ H H H H COSMe —(CH₂)₄— M-17 SMe H H H H COSMe —(CH₂)₄— M-18 SEt H H H H COSMe —(CH₂)₄— M-19 SPr^(i) H H H H COSMe —(CH₂)₄— M-20 NMe₂ H H H H COSMe —(CH₂)₄— M-21 NE₂ H H H H COSMe —(CH₂)₄— M-22 H Cl H H H COSMe —(CH₂)₄— M-23 H Br H H H COSMe —(CH₂)₄— M-24 H Me H H H COSMe —(CH₂)₄— M-25 H Et H H H COSMe —(CH₂)₄—

TABLE 75

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ M-26 H Pr H H H COSMe —(CH₂)₄— M-27 H Pr^(i) H H H COSMe —(CH₂)₄— M-28 H Bu H H H COSMe —(CH₂)₄— M-29 H Bu^(i) H H H COSMe —(CH₂)₄— M-30 H Bu^(s) H H H COSMe —(CH₂)₄— M-31 H Bu^(t) H H H COSMe —(CH₂)₄— M-32 H OMe H H H COSMe —(CH₂)₄— M-33 H OEt H H H COSMe —(CH₂)₄— M-34 H OPr H H H COSMe —(CH₂)₄— M-35 H OPr^(i) H H H COSMe —(CH₂)₄— M-36 H OCHF₂ H H H COSMe —(CH₂)₄— M-37 H OCF₃ H H H COSMe —(CH₂)₄— M-38 H CF₃ H H H COSMe —(CH₂)₄— M-39 H SMe H H H COSMe —(CH₂)₄— M-40 H SEt H H H COSMe —(CH₂)₄— M-41 H SPr^(i) H H H COSMe —(CH₂)₄— M-42 H NMe₂ H H H COSMe —(CH₂)₄— M-43 H NEt₂ H H H COSMe —(CH₂)₄— M-44 H H Cl H H COSMe —(CH₂)₄— M-45 H H Br H H COSMe —(CH₂)₄— M-46 H H Me H H COSMe —(CH₂)₄— M-47 H H Et H H COSMe —(CH₂)₄— M-48 H H Pr H H COSMe —(CH₂)₄— M-49 H H Pr^(i) H H COSMe —(CH₂)₄— M-50 H H Bu H H COSMe —(CH₂)₄—

TABLE 76

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ M-51 H H Bu^(i) H H COSMe —(CH₂)₄— M-52 H H Bu^(s) H H COSMe —(CH₂)₄— M-53 H H Bu^(t) H H COSMe —(CH₂)₄— M-54 H H OMe H H COSMe —(CH₂)₄— M-55 H H OEt H H COSMe —(CH₂)₄— M-56 H H OPr H H COSMe —(CH₂)₄— M-57 H H OPr^(i) H H COSMe —(CH₂)₄— M-58 H H OCHF₂ H H COSMe —(CH₂)₄— M-59 H H OCF₃ H H COSMe —(CH₂)₄— M-60 H H CF₃ H H COSMe —(CH₂)₄— M-61 H H SMe H H COSMe —(CH₂)₄— M-62 H H SEt H H COSMe —(CH₂)₄— M-63 H H SPr^(i) H H COSMe —(CH₂)₄— M-64 H H NMe₂ H H COSMe —(CH₂)₄— M-65 H H NEt₂ H H COSMe —(CH₂)₄— M-66 Me NMe₂ H H H COSMe —(CH₂)₄— M-67 NMe₂ Cl H H H COSMe —(CH₂)₄— M-68 Me NEt₂ H H H COSMe —(CH₂)₄— M-69 H NEt₂ Me H H COSMe —(CH₂)₄— M-70 Bu^(s) H H H H COSMe —(CH₂)₄— M-71 Pr^(i) H H H H COSMe —(CH₂)₄— M-72 H OMe OMe H H COSMe —(CH₂)₄— M-73 H OMe OEt H H COSMe —(CH₂)₄— M-74 H OEt OMe H H COSMe —(CH₂)₄— M-75 H OEt OEt H H COSMe —(CH₂)₄—

TABLE 77

R¹ R² R³ n R⁶ R⁷ R⁸ R-1  H H H 1 CSSMe Me Me R-2  Cl H H 1 CSSMe Me Me R-3  Br H H 1 CSSMe Me Me R-4  Me H H 1 CSSMe Me Me R-5  Et H H 1 CSSMe Me Me R-6  Pr H H 1 CSSMe Me Me R-7  Bu H H 1 CSSMe Me Me R-8  Bu^(i) H H 1 CSSMe Me Me R-9  Bu^(t) H H 1 CSSMe Me Me R-11 Pr^(i) H H 1 CSSMe Me Me R-11 OEt H H 1 CSSMe Me Me R-12 OPr^(i) H H 1 CSSMe Me Me R-13 OPr H H 1 CSSMe Me Me R-14 OCHF₂ H H 1 CSSMe Me Me R-15 OCF₃ H H 1 CSSMe Me Me R-16 CF₃ H H 1 CSSMe Me Me R-17 SMe H H 1 CSSMe Me Me R-18 SEt H H 1 CSSMe Me Me R-19 SPr^(i) H H 1 CSSMe Me Me R-20 NMe₂ H H 1 CSSMe Me Me R-21 NEt₂ H H 1 CSSMe Me Me R-22 H Cl H 1 CSSMe Me Me R-23 H Br H 1 CSSMe Me Me R-24 H Me H 1 CSSMe Me Me R-25 H Et H 1 CSSMe Me Me

TABLE 78

R¹ R² R³ n R⁶ R⁷ R⁸ R-26 H Pr H 1 CSSMe Me Me R-27 H Pr^(i) H 1 CSSMe Me Me R-28 H Bu H 1 CSSMe Me Me R-29 H Bu^(i) H 1 CSSMe Me Me R-30 H Bu^(s) H 1 CSSMe Me Me R-31 H Bu^(t) H 1 CSSMe Me Me R-32 H OMe H 1 CSSMe Me Me R-33 H OEt H 1 CSSMe Me Me R-34 H OPr H 1 CSSMe Me Me R-35 H OPr^(i) H 1 CSSMe Me Me R-36 H OCHF₂ H 1 CSSMe Me Me R-37 H OCF₃ H 1 CSSMe Me Me R-38 H CF₃ H 1 CSSMe Me Me R-39 H SMe H 1 CSSMe Me Me R-40 H SEt H 1 CSSMe Me Me R-4t H SPr^(i) H 1 CSSMe Me Me R-42 H NMe₂ H 1 CSSMe Me Me R-43 H NEt₂ H 1 CSSMe Me Me R-44 Cl H Cl 1 CSSMe Me Me R-45 H H Br 1 CSSMe Me Me R-46 H H Me 1 CSSMe Me Me R-47 H H Et 1 CSSMe Me Me R-48 H H Pr 1 CSSMe Me Me R-49 H H Pr^(i) 1 CSSMe Me Me R-50 H H Bu 1 CSSMe Me Me

TABLE 79

R¹ R² R³ n R⁶ R⁷ R⁸ R-51 H H Bu^(i) 1 CSSMe Me Me R-52 H H Bu^(s) 1 CSSMe Me Me R-53 H H Bu^(t) 1 CSSMe Me Me R-54 H H OMe 1 CSSMe Me Me R-55 H H OEt 1 CSSMe Me Me R-56 H H OPr 1 CSSMe Me Me R-57 H H OPr^(i) 1 CSSMe Me Me R-58 H H OCHF₂ 1 CSSMe Me Me R-59 H H OCF₃ 1 CSSMe Me Me R-60 H H CF₃ 1 CSSMe Me Me R-61 H H SMe 1 CSSMe Me Me R-62 H H SEt 1 CSSMe Me Me R-63 H H SPr^(i) 1 CSSMe Me Me R-64 H H NMe₂ 1 CSSMe Me Me R-65 H H NEt₂ 1 CSSMe Me Me R-66 Me NMe₂ H 1 CSSMe Me Me R-67 NMe₂ Cl H 1 CSSMe Me Me R-68 Me NEt₂ H 1 CSSMe Me Me R-69 H NEt₂ Me 1 CSSMe Me Me R-70 Bu^(s) H H 1 CSSMe Me Me R-71 OMe H OMe 1 CSSMe Me Me R-72 H OMe OMe 1 CSSMe Me Me R-73 H OMe OEt 1 CSSMe Me Me R-74 H OEt OMe 1 CSSMe Me Me R-75 H OEt OEt 1 CSSMe Me Me

TABLE 80

R¹ R² R³ n R⁶ R⁷ R⁸ O-1  H H H 2 CSSMe Me Me O-2  Cl H H 2 CSSMe Me Me O-3  Br H H 2 CSSMe Me Me O-4  Me H H 2 CSSMe Me Me O-5  Et H H 2 CSSMe Me Me O-6  Pr H H 2 CSSMe Me Me O-7  Bu H H 2 CSSMe Me Me O-8  Bu^(i) H H 2 CSSMe Me Me O-9  Bu^(t) H H 2 CSSMe Me Me O-10 Pr^(i) H H 2 CSSMe Me Me O-11 OEt H H 2 CSSMe Me Me O-12 OPr^(i) H H 2 CSSMe Me Me O-13 OPr H H 2 CSSMe Me Me O-14 OCHF₂ H H 2 CSSMe Me Me O-15 OCF₃ H H 2 CSSMe Me Me O-16 CF₃ H H 2 CSSMe Me Me O-17 SMe H H 2 CSSMe Me Me O-18 SEt H H 2 CSSMe Me Me O-19 SPr^(i) H H 2 CSSMe Me Me O-20 NMe₂ H H 2 CSSMe Me Me O-21 NEt₂ H H 2 CSSMe Me Me O-22 H Cl H 2 CSSMe Me Me O-23 H Br H 2 CSSMe Me Me O-24 H Me H 2 CSSMe Me Me O-25 H Et H 2 CSSMe Me Me

TABLE 81

R¹ R² R³ m R⁶ R⁷ R⁸ O-26 H Pr H 2 CSSMe Me Me O-27 H Pr^(i) H 2 CSSMe Me Me O-28 H Bu H 2 CSSMe Me Me O-29 H Bu^(i) H 2 CSSMe Me Me O-30 H Bu^(s) H 2 CSSMe Me Me O-31 H Bu^(t) H 2 CSSMe Me Me O-32 H OMe H 2 CSSMe Me Me O-33 H OEt H 2 CSSMe Me Me O-34 H OPr H 2 CSSMe Me Me O-35 H OPr^(i) H 2 CSSMe Me Me O-36 H OCHF₂ H 2 CSSMe Me Me O-37 H OCF₃ H 2 CSSMe Me Me O-38 H CF₃ H 2 CSSMe Me Me O-39 H SMe H 2 CSSMe Me Me O-40 H SEt H 2 CSSMe Me Me O-41 H SPr H 2 CSSMe Me Me O-42 H NMe₂ H 2 CSSMe Me Me O-43 H NEt₂ H 2 CSSMe Me Me O-44 F H F 2 CSSMe Me Me O-45 H H Br 2 CSSMe Me Me O-46 H H Me 2 CSSMe Me Me O-47 H H Et 2 CSSMe Me Me O-48 H H Pr 2 CSSMe Me Me O-49 H H Pr^(i) 2 CSSMe Me Me O-50 H H Bu 2 CSSMe Me Me

TABLE 82

R¹ R² R³ n R⁶ R⁷ R⁸ O-51 H H Bu^(i) 2 CSSMe Me Me O-52 H H Bu^(s) 2 CSSMe Me Me O-53 H H Bu^(t) 2 CSSMe Me Me O-54 H H OMe 2 CSSMe Me Me O-55 H H OEt 2 CSSMe Me Me O-56 H H OPr 2 CSSMe Me Me O-57 H H OPr^(i) 2 CSSMe Me Me O-58 H H OCHF₂ 2 CSSMe Me Me O-59 H H OCF₃ 2 CSSMe Me Me O-60 H H CF₃ 2 CSSMe Me Me O-61 H H SMe 2 CSSMe Me Me O-62 H H SEt 2 CSSMe Me Me O-63 H H SPr^(i) 2 CSSMe Me Me O-64 H H NMe₂ 2 CSSMe Me Me O-65 H H NEt₂ 2 CSSMe Me Me O-66 Me NMe₂ H 2 CSSMe Me Me O-67 NMe₂ Cl H 2 CSSMe Me Me O-68 Me NEt₂ H 2 CSSMe Me Me O-69 H NEt₂ Me 2 CSSMe Me Me O-70 Bu^(s) H H 2 CSSMe Me Me O-71 OMe H OMe 2 CSSMe Me Me O-72 H OMe OMe 2 CSSMe Me Me O-73 H OMe OEt 2 CSSMe Me Me O-74 H OEt OMe 2 CSSMe Me Me O-75 H OEt OEt 2 CSSMe Me Me

TABLE 83

R¹ R² R³ n R⁶ R⁷ R⁸ P-1  H H H 1 CSSMe Et Et P-2  Cl H H 1 CSSMe Et Et P-3  Br H H 1 CSSMe Et Et P-4  Me H H 1 CSSMe Et Et P-5  Et H H 1 CSSMe Et Et P-6  Pr H H 1 CSSMe Et Et P-7  Bu H H 1 CSSMe Et Et P-8  Bu^(i) H H 1 CSSMe Et Et P-9  Bu^(t) H H 1 CSSMe Et Et P-10 Pr^(i) H H 1 CSSMe Et Et P-11 OEt H H 1 CSSMe Et Et P-12 OPr^(i) H H 1 CSSMe Et Et P-13 OPr H H 1 CSSMe Et Et P-14 OCHF₂ H H 1 CSSMe Et Et P-15 OCF₃ H H 1 CSSMe Et Et P-16 CF₃ H H 1 CSSMe Et Et P-17 SMe H H 1 CSSMe Et Et P-18 SEt H H 1 CSSMe Et Et P-19 SPr^(i) H H 1 CSSMe Et Et P-20 NMe₂ H H 1 CSSMe Et Et P-21 NEt₂ H H 1 CSSMe Et Et P-22 H Cl H 1 CSSMe Et Et P-23 H Br H 1 CSSMe Et Et P-24 H Me H 1 CSSMe Et Et P-25 H Et H 1 CSSMe Et Et

TABLE 84

R¹ R² R³ n R⁶ R⁷ R⁸ P-26 H Pr H 1 CSSMe Et Et P-27 H Pr^(i) H 1 CSSMe Et Et P-28 H Bu H 1 CSSMe Et Et P-29 H Bu^(i) H 1 CSSMe Et Et P-30 H Bu^(s) H 1 CSSMe Et Et P-31 H Bu^(t) H 1 CSSMe Et Et P-32 H OMe H 1 CSSMe Et Et P-33 H OEt H 1 CSSMe Et Et P-34 H OPr H 1 CSSMe Et Et P-35 H OPr^(i) H 1 CSSMe Et Et P-36 H OCHF₂ H 1 CSSMe Et Et P-37 H OCF₃ H 1 CSSMe Et Et P-38 H CF₃ H 1 CSSMe Et Et P-39 H SMe H 1 CSSMe Et Et P-40 H SEt H 1 CSSMe Et Et P-41 H SPr^(i) H 1 CSSMe Et Et P-42 H NMe₂ H 1 CSSMe Et Et P-43 H NEt₂ H 1 CSSMe Et Et P-44 OMe H H 1 CSSMe Et Et P-45 H H Br 1 CSSMe Et Et P-46 H H Me 1 CSSMe Et Et P-47 H H Et 1 CSSMe Et Et P-48 H H Pr 1 CSSMe Et Et P-49 H H Pr^(i) 1 CSSMe Et Et P-50 H H Bu 1 CSSMe Et Et

TABLE 85

R¹ R² R³ n R⁶ R⁷ R⁸ P-51 H H Bu^(i) 1 CSSMe Et Et P-52 H H Bu^(s) 1 CSSMe Et Et P-53 H H Bu^(t) 1 CSSMe Et Et P-54 H H OMe 1 CSSMe Et Et P-55 H H OEt 1 CSSMe Et Et P-56 H H OPr 1 CSSMe Et Et P-57 H H OPr^(i) 1 CSSMe Et Et P-58 H H OCHF₂ 1 CSSMe Et Et P-59 H H OCF₃ 1 CSSMe Et Et P-60 H H CF₃ 1 CSSMe Et Et P-61 H H SMe 1 CSSMe Et Et P-62 H H SEt 1 CSSMe Et Et P-63 H H SPr^(i) 1 CSSMe Et Et P-64 H H NMe₂ 1 CSSMe Et Et P-65 H H NEt₂ 1 CSSMe Et Et P-66 Me NMe₂ H 1 CSSMe Et Et P-67 NMe₂ Cl H 1 CSSMe Et Et P-68 Me NEt₂ H 1 CSSMe Et Et P-69 H NEt₂ Me 1 CSSMe Et Et P-70 Bu^(s) H H 1 CSSMe Et Et P-71 OMe H OMe 1 CSSMe Et Et P-72 H OMe OMe 1 CSSMe Et Et P-73 H OMe OEt 1 CSSMe Et Et P-74 H OEt OMe 1 CSSMe Et Et P-75 H OEt OEt 1 CSSMe Et Et

TABLE 86

R¹ R² R³ n R⁶ R⁷ R⁸ Q-1  H H H 2 CSSMe Et Et Q-2  Cl H H 2 CSSMe Et Et Q-3  Br H H 2 CSSMe Et Et Q-4  Me H H 2 CSSMe Et Et Q-5  Et H H 2 CSSMe Et Et Q-6  Pr H H 2 CSSMe Et Et Q-7  Bu H H 2 CSSMe Et Et Q-8  Bu^(i) H H 2 CSSMe Et Et Q-9  Bu^(t) H H 2 CSSMe Et Et Q-10 Pr^(i) H H 2 CSSMe Et Et Q-11 OEt H H 2 CSSMe Et Et Q-12 OPr^(i) H H 2 CSSMe Et Et Q-13 OPr H H 2 CSSMe Et Et Q-14 OCHF₂ H H 2 CSSMe Et Et Q-15 OCF₃ H H 2 CSSMe Et Et Q-16 CF₃ H H 2 CSSMe Et Et Q-17 SMe H H 2 CSSMe Et Et Q-18 SEt H H 2 CSSMe Et Et Q-19 SPr^(i) H H 2 CSSMe Et Et Q-20 NMe₂ H H 2 CSSMe Et Et Q-21 NEt₂ H H 2 CSSMe Et Et Q-22 H Cl H 2 CSSMe Et Et Q-23 H Br H 2 CSSMe Et Et Q-24 H Me H 2 CSSMe Et Et Q-25 H Et H 2 CSSMe Et Et

TABLE 87

R¹ R² R³ m R⁶ R⁷ R⁸ Q-26 H Pr H 2 CSSMe Et Et Q-27 H Pr^(i) H 2 CSSMe Et Et Q-28 H Bu H 2 CSSMe Et Et Q-29 H Bu^(i) H 2 CSSMe Et Et Q-30 H Bu^(s) H 2 CSSMe Et Et Q-31 H Bu^(t) H 2 CSSMe Et Et Q-32 H OMe H 2 CSSMe Et Et Q-33 H OEt H 2 CSSMe Et Et Q-34 H OPr H 2 CSSMe Et Et Q-35 H OPr^(i) H 2 CSSMe Et Et Q-36 H OCHF₂ H 2 CSSMe Et Et Q-37 H OCF₃ H 2 CSSMe Et Et Q-38 H CF₃ H 2 CSSMe Et Et Q-39 H SMe H 2 CSSMe Et Et Q-40 H SEt H 2 CSSMe Et Et Q-41 H SPr^(i) H 2 CSSMe Et Et Q-42 H NMe₂ H 2 CSSMe Et Et Q-43 H NEt₂ H 2 CSSMe Et Et Q-44 OMe H H 2 CSSMe Et Et Q-45 H H Br 2 CSSMe Et Et Q-46 H H Me 2 CSSMe Et Et Q-47 H H Et 2 CSSMe Et Et Q-48 H H Pr 2 CSSMe Et Et Q-49 H H Pr^(i) 2 CSSMe Et Et Q-50 H H Bu 2 CSSMe Et Et

TABLE 88

R¹ R² R³ n R⁶ R⁷ R⁸ Q-51 H H Bu^(i) 2 CSSMe Et Et Q-52 H H Bu^(s) 2 CSSMe Et Et Q-53 H H Bu^(t) 2 CSSMe Et Et Q-54 H H OMe 2 CSSMe Et Et Q-55 H H OEt 2 CSSMe Et Et Q-56 H H OPr 2 CSSMe Et Et Q-57 H H OPr^(i) 2 CSSMe Et Et Q-58 H H OCHF₂ 2 CSSMe Et Et Q-59 H H OCF₃ 2 CSSMe Et Et Q-60 H H CF₃ 2 CSSMe Et Et Q-61 H H SMe 2 CSSMe Et Et Q-62 H H SEt 2 CSSMe Et Et Q-63 H H SPr^(i) 2 CSSMe Et Et Q-64 H H NMe₂ 2 CSSMe Et Et Q-65 H H NEt₂ 2 CSSMe Et Et Q-66 Me NMe₂ H 2 CSSMe Et Et Q-67 NMe₂ Cl H 2 CSSMe Et Et Q-68 Me NEt₂ H 2 CSSMe Et Et Q-69 H NEt₂ Me 2 CSSMe Et Et Q-70 Bu^(s) H H 2 CSSMe Et Et Q-71 OMe H OMe 2 CSSMe Et Et Q-72 H OMe OMe 2 CSSMe Et Et Q-73 H OMe OEt 2 CSSMe Et Et Q-74 H OEt OMe 2 CSSMe Et Et Q-75 H OEt OEt 2 CSSMe Et Et

The above compounds of the present invention were examined as shown below.

Example 1 Experiments for Human CB2 Receptor (CB2R) Binding Inhibition

The coding region of human CB2R cDNA (Munro etc, Nature, 1993, 365, 61-65) was inserted into the mammalian expression vector, pSVL SV40 Late Promoter Expression Vector (Amersham Pharmacia Biotech Inc.). The prepared vector was transfected into Chinese Hamster Ovary (CHO) cells with LipofectAMINE reagent (Gibco BRL) according to the manufacture's protocol, and the stable CB2R-expressing clones were selected.

The crude membrane fractions were then prepared from the CB2R-expressing CHO cells. Receptor binding assay was performed by incubating the membranes with each test compound and [³H]CP55940 (at a final concentration of 0.5 nM: NEN Life Science Products) in the assay buffer (50 mM Tris-HCl, 1 mM EDTA, 3 mM MgCl2, pH 7.4) containing 0.5% bovine serum albumin (BSA) for 2 hr at 25° C. The incubation mixture was filtered through 1% polyethylenimine (PEI)-treated GF/C glass filter and washed with 50 mM Tris-HCl (pH 7.4) containing 0.1% BSA. The radioactivity was then counted with a liquid scintillation counter. Nonspecific binding was determined in the presence of 10 μM WIN55212-2 (a CB agonist described in the U.S. Pat. No. 5,081,22, Research Biochemicals International), and the specific binding was calculated by subtracting the nonspecific binding from the total binding. The IC₅₀ value for each test compound was determined as the concentration at which 50% of the specific binding was inhibited.

For the receptor binding assay of human CB1 receptor (CB1R), the stable CB1R-expressing CHO cells were prepared as described above, and the binding assay was performed with their membrane fractions. As a consequence of these studies, the Ki values of each test compound for both cannabinoid receptors were determined, which were presented in Table 89. As shown in this table, a series of compounds described in the present invention were found to selectively block the binding of CP55940 (a CB agonist described in the U.S. Pat. No. 4,371,720) to CB2R more effectively than CB1R. TABLE 89 Compound Ki (nM) No. CB1receptor CB2receptor I-5  >5000 61 I-23 >5000 29 I-50 >5000 39 I-51 n.t. 23 I-52 n.t. 35 I-56 n.t. 54 I-6  >5000 9 I-57 4134 6 I-69 n.t. 33 I-60 2097 18 I-62 n.t. 44 I-63 n.t. 43 I-74 n.t. 48 I-77 n.t. 53 I-84 >5000 35 I-85 n.t. 25 n.t.: not tested

Example 2 Inhibition Experiments for CB2R-Mediated Suppression of cAMP Synthesis

The CHO cells expressing human CB2R were incubated with test compounds for 15 min. After the incubation, 4 μM forskolin (Sigma) was added and the cells were incubated for 20 min at 37° C. The reaction was stopped by the addition of 1N HCl and the amount of cAMP in the cell supernatant was measured using an EIA kit (Amersham Pharmacia Biotech) according to the manufacture's protocol. The cAMP amount increased by forskolin compared to that in the absence of forskolin was defined as 100%, and the IC₅₀ value of each test compound was determined as the concentration at which 50% of the forskolin-stimulated cAMP synthesis was inhibited. As a consequence of these studies, the IC₅₀ value of each test compound was presented in Table 90. As shown in Table 90, the compounds described in the present invention were found to possess agonistic activity toward CB2R.

The antagonistic activity of each compound was also evaluated in this assay. TABLE 90 Compound No. IC₅₀ (nM) I-5  6.5 I-23 2.6 I-51 2.8 I-6  2.7 I-57 5.5

Example 3 Experiments for Sheep Red Blood Cell (SRBC)-Induced Delayed Type Hypersensitive (DTH) Reaction

Female ddY mice (7 weeks old) were used for the sheep red blood cell (SRBC)-induced delayed type hypersensitive (DTH) reaction.

Cannabinoid receptor agonist, I-6, I-60, I-77 and I-118 were suspended in 0.6% arabic gum solution. Mice were sensitized by the intradermal injection of 10⁷ cells of SRBC (40 μl/foot) into the left hind foot pad. After 5 days, DTH reaction was induced by the intradermal injection of 10⁸ cells of SRBC in the right hind foot pad. Test compounds were administerd p.o. (10 ml/kg) 1 hr before and 5 hr after the induction of DTH reaction. After 24 hrs of the injection of SRBC, the left and right foot pad volumes were measured by the water displacement method. The foot pad swelling was calculated as the differences in the volumes between the right and left hind foot pad, and used as an index of the DTH reaction.

Data are expressed as the inhibition percentage of each compound. Statistical analysis was performed with Welch's t-test, in which the value of P<0.05 is considered as a significant difference. TABLE 91 Inhibition Comp. percentage No. Dose (mg/kg) (%) I-6  40 45.2 I-6O 30 31.1 I-77 30 33.8  I-118 30 33.0

INDUSTRIAL APPLICABILITY

The compound of the formula (I) and (II) of the present invention selectively binds to the cannabinoid type 2 receptor (CB2R) to exhibit an antagonistic activity or agonistic activity to CB2R. Therefore, the present compound neither causes side effects on the central nervous system such as illusion or the drug dependence associated with the cannabinoid type 1 receptor (CB1R) and can be used for treating or preventing diseases associated with the cannabinoid type 2 receptor (CB2R). 

1-7. (canceled)
 8. A compound of the formula (II):

wherein R¹ is optionally substituted alkylene, R² is a group of the formula: —C(═R⁵)—R⁶ wherein R⁵ is O or S, R⁶ is alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aralkyloxy, optionally substituted aralkylthio, optionally substituted aralkylamino, alkoxyalkyl, alkylthioalkyl, or optionally substituted aminoalkyl; or a group of formula: —SO₂R⁷ wherein R⁷ is alkyl, optionally substituted amino, optionally substituted aryl or optionally substituted heteroaryl, R³ and R⁴ each is independently hydrogen, alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substitute aryl, optionally substituted aryloxy, cycloalkyl, halogen, hydroxy, nitro, haloalkyl, haloalkoxy, optionally substituted carbamoyl, carboxy, alkoxycarbonyl, alkylsulfinyl, alkysulfonyl, alkoxyalkyl, alkylthioalkyl, optionally substituted aminoalkyl, alkoxyalkoxy, alkylthioalkoxy, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclic group, alkoxyiminoalkyl, or a group of the formula: —C(═O)—R^(H) wherein R^(H) is hydrogen, alkyl, optionally substituted aryl or optionally substituted non-aromatic heterocyclic group, or R³ and R⁴ taken together may form alkylenedioxy, m is an integer of 0 to 2, A is optionally substituted aromatic carbocycle or optionally substituted aromatic heterocycle, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
 9. The compound according to claim 8 wherein m is 0, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
 10. The compound according to claim 8 wherein R¹ is a C2-C9 straight or branched alkylene optionally substituted with alkylene, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
 11. The compound according to claim 8 wherein R¹ is a C2-C9 straight alkylene substituted with alkylene, or a C2-C9 branched alkylene, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
 12. The compound according to claim 8 wherein R⁶ is alkoxy or alkylthio, and R⁷ is optionally substituted aryl, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
 13. The compound according to claim 8 wherein R³ and R⁴ each is independently hydrogen, alkyl, alkoxy or alkylthio, and A is optionally substituted aromatic carbocycle, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
 14. The compound according to claim 8 wherein R¹ is 2,2-dimethyltrimethylene, 2,2-diethyltrimethylene, 2,2-ethylenetrimethylene, 1-methyltrimethylene, 2-methyltrimethylene, trimethylene, 2,2-di-n-propyltrimethylene, 2,2-tetramethylenetrimethylene, 2,2-pentamethylenetrimethylene, 1,1-dimethylethylene or 1-methylethylene, R6 is methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, methylthio, ethylthio, n-propylthio, i-propylthio, i-butylthio, sec-butylthio, benzyloxy, benzylthio, methoxymethyl, ethoxymethyl, methylthiomethyl, ethylthiomethyl or ethylamino, R⁷ is methyl, ethyl, 4-tolyl, 4-nitrophenyl, 3-nitrophenyl, 2-nitrophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-thienyl or 2-naphthyl, R³ is hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, methylthio, ethylthio, n-propylthio, i-propylthio, dimethylamino, acetylamino, N-acetylmethylamino, diethylamino, ethylmethylamino, propylmethylamino, phenyl, phenoxy, fluoro, chloro, bromo, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, N-methylcarbamoyl, methoxycarbonyl, methanesulfinyl, ethanesulfinyl, methanesulfonyl, ethanesulfonyl, acetyl, methoxymethyl, 1-methoxyethyl, 3-pyridyl, morpholino, pyrrolidino, piperidino, 2-oxopyrrolidino, 1-methoxyiminoethyl or morpholinocarbonyl, R⁴ is hydrogen, methyl, ethyl, fluoro, cholro, nitro, methoxy or ethoxy, or R³ and R⁴ taken together may form —O—CH₂—O—, A is benzene, naphthalene, pyridine or quinoline, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
 15. A pharmaceutical composition which comprises the compound according to claim 8, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
 16. The pharmaceutical composition according to claim 15 which has a binding activity to a cannabinoid type 2 receptor.
 17. The pharmaceutical composition according to claim 16 which has an agonistic activity to a cannabinoid type 2 receptor.
 18. The pharmaceutical composition according to claim 16 which is useful as an anti-inflammatory agent.
 19. The pharmaceutical composition according to claim 16 which is useful as an immunosuppressive agent.
 20. The pharmaceutical composition according to claim 16 which is useful as a nephritis treating agent.
 21. A method for treating inflammation which comprises administering the pharmaceutical composition according to claim 8 to a patient in need thereof.
 22. A method of immunosuppression which comprises administering the pharmaceutical composition according to claim 8 to a patient in need thereof.
 23. A method for treating nephritis which comprises administering the pharmaceutical composition according to claim 8 to a patient in need thereof. 24-26. (canceled)
 27. The compound according to claim 8, wherein A is optionally substituted naphthalene.
 28. The compound according to claim 8, which has the formula:

wherein A is optionally substituted naphthalene; R⁶ is CSSMe R⁷ is Me; and R⁸ is Me, a prodrug thereof, a pharmaceutically acceptable salt thereof or solvate thereof. 